Neutral pH compositions of Docetaxel and human serum albumin

ABSTRACT

This document relates to non-covalently bound complexes including Docetaxel and human serum albumin, and to compositions comprising such complexes. This document also relates to compositions comprising Docetaxel and human serum albumin, wherein the composition is a clear aqueous solution when the composition is dissolved in an aqueous solution, and wherein the composition has a solubility in an aqueous solution of at least 10 mg/ml. This document also relates to compositions comprising Docetaxel and human serum albumin, wherein the Docetaxel and the human serum albumin in the composition have a weight ratio from about 1:50 to about 1:1000. This document also relates to compositions consisting essentially of Docetaxel and human serum albumin, wherein the Docetaxel and the human serum albumin in the composition have a weight ratio from about 1:50 to about 1:1000. The pH of the docetaxel compositions of the present disclosure is from about 5 to about 8.

CLAIM OF PRIORITY

This application is a 371 U.S. National Application ofPCT/US2017/058697, filed Oct. 27, 2017, which claims the benefit of U.S.Provisional Patent Applications Ser. No. 62/413,603, filed on Oct. 27,2016, and Ser. No. 62/420,397, filed on Nov. 10, 2016. The entirecontents of the foregoing are hereby incorporated by reference.

TECHNICAL FIELD

This document relates to complexes and compositions for the treatment ofproliferative diseases, and more particularly to complexes andcompositions comprising Docetaxel and human serum albumin, wherein pH ofthe compositions is neutral.

BACKGROUND

Many drugs for parenteral use are insoluble in water, and are thusformulated with solubilizing agents, surfactants, solvents, and/oremulsifiers that are irritating, allergenic, or toxic when administeredto patients. See, e.g., Briggs et al., Anesthesis 37, 1099 (1982), andWaugh et al., Am. J. Hosp. Pharmacists, 48, 1520 (1991)). Further, manyof these drugs, especially those administered intravenously, causeundesirable side effects such as venous irritation, phlebitis, burningand pain on injection, venous thrombosis, extravasation, and otheradministration related side effects. Additionally, often free drugspresent in formulations induce pain or irritation upon administration.

Taxanes play an important role in the treatment of various solid tumors.As a second-generation semi-synthetic taxane derivative, Docetaxel isabout twice as potent as paclitaxel in habiting microtubuledepolymerization, and has the unique ability to alter certain classes ofmicrotubules, which differs from most spindle poisons currently used inclinic. However, Docetaxel has very poor water solubility. The clinicalintravenous administration of commercially available Docetaxel(Taxotere®) is formulated in a highly concentrated solution containing40 mg Docetaxel and 1040 mg Polysorbate 80 per mL. This concentratedsolution must be carefully diluted with solvent containing 13% ethanolin saline before administration, and must be used within 4 hours due toits limited stability. These attributes limit the administration ofDocetaxel. Further, it has been reported that docetaxel administrationis associated with the occurrence of unpredictable (acute)hypersensitivity reactions and cumulative fluid retention. See, e.g.,Trudeau M E et al., J Clin Oncol 1996; 14:422-8, Piccart M J et al., JNatl Cancer Inst 1995; 87:676-81, Bruno R et al., J Clin Oncol 1998;16:187-96. These side-effects have been attributed, in part, to thepresence of polysorbate 80.

US 2005/0282734 describes complexes of paclitaxel and albumin.Successful formulations described in this document require acidic pH.

WO 2014/121033 describes complexes of camptothecin and albumin.

US 2012/0076862 describes nanoparticles of taxane and albumin.

US 2010/0076008 describe paclitaxel non-covalently bound to HSA.

WO 2016/187147 describes complexes of docetaxel and albumin.

Accordingly, there is a need in the art for stable and non-toxicformulations of Docetaxel. The compositions and methods described in thepresent application help meet this need.

SUMMARY

Provided herein are non-covalently bound complexes including Docetaxeland human serum albumin, wherein the Docetaxel and the human serumalbumin are in a molar ratio from about 0.1:1 to about 5:1. In someembodiments, the pH of a composition comprising the non-covalently boundcomplexes including Docetaxel and human serum albumin is neutral (e.g.,pH of the composition is from about 5 to about 8, from about 5.5 toabout 7.5, or from about 6 to about 7, or the pH of the composition isabout 5, about 5.5, about 6, about 6.4, about 6.5, about 6.6, about 7,about 7.5 or about 8).

In some embodiments, the Docetaxel and the human serum albumin have amolar ratio from about 0.1:1 to about 3:1, from about 0.5:1 to about2:1, from about 0.75:1 to about 1.5:1, or from about 0.8:1 to about1.3:1. In some embodiments, the Docetaxel and the human serum albuminhave a molar ratio of about 0.5:1, about 0.6:1, about 0.7:1, about0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1,about 1.4:1, or about 1.5:1.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free.

Also, provided herein is a non-covalently bound complex includingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin are in a molar ratio from about 0.1:1 to about 5:1.

The present application also provides a non-covalently bound complexcomprising Docetaxel and human serum albumin, wherein molar ratio of theDocetaxel and the human serum albumin in the complex is from about 0.1:1to about 5:1.

In some embodiments, the molar ratio of Docetaxel and the human serumalbumin in the complex is from about 0.1:1 to about 3:1, from about0.5:1 to about 2:1, from about 0.75:1 to about 1.5:1, or from about0.8:1 to about 1.3:1. In some embodiments, the Docetaxel and the humanserum albumin have a molar ratio of about 0.5:1, about 0.6:1, about0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1,about 1.3:1, about 1.4:1, or about 1.5:1.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free.

Also, provided herein is a composition comprising a non-covalently boundcomplex including Docetaxel and human serum albumin, wherein theDocetaxel and the human serum albumin in the composition have a molarratio from about 0.1:1 to about 5:1. In some embodiments, the Docetaxeland the human serum albumin have a molar ratio from about 0.1:1 to about3:1, from about 0.5:1 to about 3:1, from about 0.5:1 to about 2:1, fromabout 0.75:1 to about 1.5:1, or from about 0.8:1 to about 1.3:1. In someembodiments, the Docetaxel and the human serum albumin have a molarratio of about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1,about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1,about 2.3:1, about 2.4:1, or about 2.5:1. In some embodiments, the pH ofthe composition comprising a non-covalently bound complex includingDocetaxel and human serum albumin is neutral (e.g., pH of thecomposition is from about 5 to about 8, from about 5.5 to about 7.5, orfrom about 6 to about 7, or the pH of the composition is about 5, about5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free.

In some embodiments, the composition is a solid formulation. Forexample, the solid formulation can be produced in a uniform manner bylyophilization. A skilled artisan would recognize other methods, such asrotary evaporation, that can also produce solid formulations. In someembodiments, the pH of the solid formulation is neutral (e.g., pH of thecomposition is from about 5 to about 8, from about 5.5 to about 7.5, orfrom about 6 to about 7, or the pH of the composition is about 5, about5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the composition is an aqueous formulation. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water. In some embodiments, the aqueousformulation includes water and water-miscible organic solvents includingat least one of polyethylene glycol 300, polyethylene glycol 400,ethanol, methanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide. For example, thewater-miscible organic solvent can include ethanol. In some embodiments,the aqueous formulation includes water and ethanol. In some embodiments,the water-miscible organic solvent can be a mixture of water-miscibleorganic solvents.

In some embodiments, the aqueous formulation can be free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation can be substantially free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation is free of surfactants selectedfrom the group selected from CREMOPHOR® surfactants and Polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueoussolution. For example, the formulation can be a clear and stable aqueoussolution reconstituted from a sterile lyophilized powder. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation is substantially free of solvent otherthan water. In some embodiments, the aqueous formulation is a clearaqueous solution, wherein the aqueous formulation is free of solventother than water. In some embodiments, the pH of the aqueous formulation(e.g., clear aqueous solution) is neutral (e.g., pH of the compositionis from about 5 to about 8, from about 5.5 to about 7.5, or from about 6to about 7, or the pH of the composition is about 5, about 5.5, about 6,about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3,about 7.4, about 7.5 or about 8).

Also, provided herein is a pharmaceutical composition comprising thecomposition comprising a non-covalently bound complex including theDocetaxel and the human serum albumin as described herein, and apharmaceutically acceptable carrier.

Also, provided herein is a method of treating a cancer, the methodcomprising the step of administering to a subject in need thereof of atherapeutically effective amount of a pharmaceutical compositioncomprising the composition comprising a non-covalently bound complexcomprising the Docetaxel and the human serum albumin as describedherein, and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is a solid tumor cancer. In someembodiments, the cancer is selected from the group consisting of breastcancer, non-small cell lung cancer, prostate cancer, gastric cancer,head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi'ssarcoma. In some embodiments, the cancer is a breast cancer. In someembodiments, the cancer is a non-small cell lung cancer. In someembodiments, the cancer is a prostate cancer. In some embodiments, thecancer is a gastric cancer. In some embodiments, the cancer is a headand neck cancer. In some embodiments the cancer is an ovarian cancer. Insome embodiments, the cancer is a pancreatic cancer. In someembodiments, the cancer is a Kaposi's sarcoma.

Also, provided herein is a composition comprising Docetaxel and humanserum albumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 0.1:1 to about 5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the composition has asolubility in an aqueous solution of at least 10 mg/ml. In some aspectsof these embodiments, the pH of the composition is neutral (e.g., pH ofthe composition is from about 5 to about 8, from about 5.5 to about 7.5,or from about 6 to about 7, or the pH of the composition is about 5,about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1,about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the Docetaxel and the human serum albumin have amolar ratio from about 0.1:1 to about 3:1, from about 0.2:1 to about3:1, from about 0.2:1 to about 2:1, from about 0.5:1 to about 2:1, fromabout 0.75:1 to about 1.5:1, or from about 0.8:1 to about 1.3:1. In someembodiments, the Docetaxel and the human serum albumin have a molarratio of about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1,about 1.2:1, about 1.3:1, about 1.4:1, or about 1.5:1, about 1.6:1,about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about2.2:1, about 2.3:1, about 2.4:1, or about 2.5:1.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free.

In some embodiments, the composition forms a clear aqueous solution forat least 6 hours when the composition is dissolved in an aqueoussolution. In some embodiments, the composition forms a clear aqueoussolution for at least 24 hours when the composition is dissolved in anaqueous solution. In some embodiments, the composition forms a clearaqueous solution for at least 3 days when the composition is dissolvedin an aqueous solution. In some embodiments, the aqueous solution issubstantially free of solvent other than water. In some embodiments, theaqueous solution is free of solvent other than water.

In some embodiments, the composition is a solid formulation. Forexample, the solid formulation can be produced in a uniform manner bylyophilization. A skilled artisan would recognize other methods, such asrotary evaporation, that can also produce solid formulations. In someaspects of these embodiments, the pH of the solid formulation is neutral(e.g., pH of the composition is from about 5 to about 8, from about 5.5to about 7.5, or from about 6 to about 7, or the pH of the compositionis about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0,about 7.1, about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the composition is an aqueous formulation. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water. In some embodiments, the aqueousformulation includes water and water-miscible organic solvents includingat least one of polyethylene glycol 300, polyethylene glycol 400,ethanol, methanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide. For example, thewater-miscible organic solvent can include ethanol. In some embodiments,the aqueous formulation includes water and ethanol. In some embodiments,the water-miscible organic solvent can be a mixture of water-miscibleorganic solvents.

In some embodiments, the aqueous formulation can be free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation can be substantially free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation is free of surfactants selectedfrom the group selected from CREMOPHOR® surfactants and Polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueoussolution. For example, the formulation can be a clear and stable aqueoussolution reconstituted from a sterile lyophilized powder. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation is substantially free of solvent otherthan water. In some embodiments, the aqueous formulation is a clearaqueous solution, wherein the aqueous formulation is free of solventother than water. In some embodiments, the solution remains clear for atleast about 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 20hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days or a week. Insome embodiments, the pH of the aqueous formulation is neutral (e.g., pHof the composition is from about 5 to about 8, from about 5.5 to about7.5, or from about 6 to about 7, or the pH of the composition is about5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1,about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

Also, provided herein is a pharmaceutical composition comprising thecomposition comprising the Docetaxel and the human serum albumin asdescribed herein, and a pharmaceutically acceptable carrier.

Also, provided herein is a method of treating a cancer, the methodcomprising the step of administering to a subject in need thereof of atherapeutically effective amount of a pharmaceutical compositioncomprising the composition comprising the Docetaxel and the human serumalbumin as described herein, and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is a solid tumor cancer. In someembodiments, the cancer is selected from the group consisting of breastcancer, non-small cell lung cancer, prostate cancer, gastric cancer,head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi'ssarcoma. In some embodiments, the cancer is a breast cancer. In someembodiments, the cancer is a non-small cell lung cancer. In someembodiments, the cancer is a prostate cancer. In some embodiments, thecancer is a gastric cancer. In some embodiments, the cancer is a headand neck cancer. In some embodiments the cancer is an ovarian cancer. Insome embodiments, the cancer is a pancreatic cancer. In someembodiments, the cancer is a Kaposi's sarcoma.

Also, provided herein is a composition comprising Docetaxel and humanserum albumin, wherein the Docetaxel and the human serum albumin in thecomposition have a ratio by weight from about 1:50 to about 1:1000. Insome embodiments, the pH of a composition is neutral (e.g., pH of thecomposition is from about 5 to about 8, from about 5.5 to about 7.5, orfrom about 6 to about 7, or the pH of the composition is about 5, about5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:50 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:60 to about 1:300. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:250. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:200. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:120. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:1000.In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight of about 1:60, about 1:70, about1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130,about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240,or about 1:250.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin isessentially fatty acid free. In some embodiments, the human serumalbumin is fatty acid free.

In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution. In someembodiments, the aqueous solution is substantially free of solvent otherthan water.

In some embodiments, the composition forms a clear aqueous solution forat least 3 hours when the composition is dissolved in an aqueoussolution. In some embodiments, the composition forms a clear aqueoussolution for at least 6 hours when the composition is dissolved in anaqueous solution. In some embodiments, the composition forms a clearaqueous solution for at least 24 hours when the composition is dissolvedin an aqueous solution. In some embodiments, the composition forms aclear aqueous solution for at least 3 days when the composition isdissolved in an aqueous solution. In some embodiments, the aqueoussolution is substantially free of solvent other than water. In someembodiments, the pH of the aqueous solution is neutral (e.g., pH of thecomposition is from about 5 to about 8, from about 5.5 to about 7.5, orfrom about 6 to about 7, or the pH of the composition is about 5, about5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the composition is a solid formulation. In someembodiments, the composition is an aqueous formulation. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof a surfactant, such as CREMOPHOR® surfactants and Polysorbate 80. Insome embodiments, the aqueous formulation is a clear aqueous solution.In some embodiments, the aqueous formulation is free of surfactantsselected from the group selected from CREMOPHOR® surfactants andPolysorbate 80. In some embodiments, the pH of the solid formulation orthe aqueous formulation is neutral (e.g., pH of the composition is fromabout 5 to about 8, from about 5.5 to about 7.5, or from about 6 toabout 7, or the pH of the composition is about 5, about 5.5, about 6,about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3,about 7.4, about 7.5 or about 8).

Also, provided herein is a pharmaceutical composition comprising thecomposition comprising the Docetaxel and the human serum albumin asdescribed herein, and a pharmaceutically acceptable carrier.

Also, provided herein is a method of treating cancer comprising the stepof administering to a subject in need thereof a therapeuticallyeffective amount of a pharmaceutical composition comprising thecomposition comprising the Docetaxel and the human serum albumin asdescribed herein, and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is a solid tumor cancer. In someembodiments, the cancer is selected from the group consisting of breastcancer, non-small cell lung cancer, prostate cancer, gastric cancer,head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi'ssarcoma. In some embodiments, the cancer is a breast cancer. In someembodiments, the cancer is a non-small cell lung cancer. In someembodiments, the cancer is a prostate cancer. In some embodiments, thecancer is a gastric cancer. In some embodiments, the cancer is a headand neck cancer. In some embodiments the cancer is an ovarian cancer. Insome embodiments, the cancer is a pancreatic cancer. In someembodiments, the cancer is a Kaposi's sarcoma.

Also, provided herein is a composition consisting essentially ofDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:50to about 1:1000.

In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:50 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:60 to about 1:300. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:250. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:200. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:120. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:1000.In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight of about 1:60, about 1:70, about1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130,about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240,or about 1:250.

DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing mean plasma concentration over time forDocetaxel after an IV dose of 680 mg/kg of the composition comprisingDocetaxel and HSA in SD rats.

DETAILED DESCRIPTION

Provided herein are non-covalently bound complexes including Docetaxeland human serum albumin, wherein the Docetaxel and the human serumalbumin are in a molar ratio from about 0.1:1 to about 5:1. In someembodiments, the pH of a composition comprising the non-covalently boundcomplexes including Docetaxel and human serum albumin is neutral (e.g.,pH of the composition is from about 5 to about 8, from about 5.5 toabout 7.5, or from about 6 to about 7, or the pH of the composition isabout 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4,about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about7.1, about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the present disclosure provides a non-covalentlybound complex comprising Docetaxel and human serum albumin, wherein themolar ratio of Docetaxel and the human serum albumin in each complex isfrom about 0.1:1 to about 5:1.

In some embodiments, the present disclosure provides non-covalentlybound complexes comprising Docetaxel and human serum albumin, whereinthe molar ratio of Docetaxel and the human serum albumin in thecomplexes is from about 0.1:1 to about 5:1.

In some embodiments, the molar ratio of Docetaxel and the human serumalbumin in the complex is from about 0.1:1 to about 3:1, from about0.5:1 to about 2:1, from about 0.75:1 to about 1.5:1, or from about0.8:1 to about 1.3:1. In some embodiments, the Docetaxel and the humanserum albumin have a molar ratio of about 0.5:1, about 0.6:1, about0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1,about 1.3:1, about 1.4:1, or about 1.5:1.

In some embodiments, the non-covalent interaction between Docetaxel andhuman serum albumin in the complex comprises hydrogen bonding. In someembodiments, the non-covalent interaction between Docetaxel and humanserum albumin in the complex comprises electrostatic interaction. Insome embodiments, the non-covalent interaction between Docetaxel andhuman serum albumin in the complex comprises hydrophobic interaction. Insome embodiments, the non-covalent interaction between Docetaxel andhuman serum albumin in the complex comprises Van der Waals forces.

As used herein, the term “human serum albumin” refers to native andrecombinant human serum albumin. Native human serum albumin and otherplasma proteins can be precipitated from human plasma by varying the pHand adding ethanol, in what is known as the Cohn fractionation process(Cohn E J et al., J. Am. Chem. Soc. 1946; 68:459-475). By controllingthe pH and ethanol content, semi-purified fractions of plasma proteinscan be produced. One of the last proteins to precipitate in the Cohnprocess is native human serum albumin. After precipitation, a wet pasteof crude native human serum albumin is obtained. Subsequentbioprocessing steps (purification, filtration, pasteurization, etc.) canbe used to produce a purified, stabilized form of native human serumalbumin for commercial use (Lin J J et al., Pharmaceutical Research2000; 17:391-6). Recombinant human serum albumin is a highly purifiedanimal-, virus-, and prion-free product as alternative to native humanserum albumin, to which it is structurally equivalent (Bosse D et al.,J. Clin. Pharmacol. 2005; 45:57-67). Recombinant human serum albumin hasbeen produced by various hosts, both prokaryotic and eukaryotic (Chen Zet al., Biochimica et Biophysica Acta 2013; 1830:5515-5525). A fattyacid free human serum albumin can be prepared by treatment of humanserum albumin with charcoal at low pH. Likewise, treatment of humanserum albumin with charcoal at low pH can be used to remove fatty acidsfrom human serum albumin (Chen R F, J. Biol. Chem. 1967; 242:173-181).Human serum albumin (HSA) is a highly soluble globular protein of M_(r)65K and consists of 585 amino acids. HSA is the most abundant protein inthe plasma and accounts for 70-80% of the colloid osmotic pressure ofhuman plasma. The amino acid sequence of HSA contains a total of 17disulphide bridges, one free thiol (Cys 34), and a single tryptophan(Trp 214). Intravenous use of HSA solution has been indicated for theprevention and treatment of hypovolumic shock (see, e.g., Tullis, JAMA,237, 355-360, 460-463, (1977) and Houser et al., Surgery, Gynecology andObstetrics, 150, 811-816 (1980)) and in conjunction with exchangetransfusion in the treatment of neonatal hyperbilirubinemia (see, e.g.,Finlayson, Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)).

Human serum albumin (HSA) has multiple hydrophobic binding sites (atotal of seven for medium and long-chain fatty acids, an endogenousligand of HSA) and binds a diverse set of drugs, especially neutral andnegatively charged hydrophobic compounds (Goodman et al., ThePharmacological Basis of Therapeutics, 9th ed, McGraw-Hill New York(1996)). Two high affinity binding sites have been proposed insubdomains IIA and IIIA of HSA, which are highly elongated hydrophobicpockets with charged lysine and arginine residues near the surface whichfunction as attachment points for polar ligand features (see, e.g.,Fehske et al., Biochem. Pharmcol., 30, 687-92 (1981), Vorum, Dan. Med.Bull., 46, 379-99 (1999), Kragh-Hansen, Dan. Med Bull., 1441, 131-40(1990), Curry et al., Nat. Struct. Biol., 5, 827-35 (1998), Sugio etal., Protein. Eng., 12, 439-46 (1999), He et al., Nature, 358, 209-15(1992), and Carter et al., Adv. Protein. Chem., 45, 153-203 (1994)).

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free. In some embodiments, thehuman serum albumin contains no more than two moles of fatty acids boundto one mole of human serum albumin. In some embodiments, the human serumalbumin contains no more than one mole of fatty acids bound to one moleof human serum albumin. In some embodiments, human serum albumincontains no more than 0.5 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.1 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.05 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.01 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.001 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0005 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0001 moles of fatty acids bound to one mole ofhuman serum albumin.

As used herein, the term “non-covalently bound complex” refers to acomplex in which the bonds between the components of the complex arenon-covalent bonds (e.g., weak bonds such as hydrogen bonds,electrostatic effects, π-effects, hydrophobic effects and Van der Waalsforces). Further, human serum albumin (HSA) has multiple hydrophobicbinding sites (a total of seven for medium and long-chain fatty acids,an endogenous ligand of HSA) and binds a diverse set of drugs,especially neutral and negatively charged hydrophobic compounds (Goodmanet al., The Pharmacological Basis of Therapeutics, 9th ed, McGraw-HillNew York (1996)). Additionally, after the drug molecule binds to HSA,the drug molecule and HSA form a non-covalently bound drug and proteincomplex through the binding sites of HSA. This concept is commonlyunderstood by one of ordinary skill in the art to which this disclosurebelongs. One example of a non-covalently bound complex is anon-covalently bound complex of HSA and fatty acids, in which the fattyacids bind to HSA through HSA's multiple binding sites.

As used herein, the term “stable” refers to non-covalently boundcomplexes that do not readily disassociate and aggregate into theirseparate parts, e.g., do not readily dissociate and aggregate for aperiod of time of greater than 6 hours, 12 hours, 24 hours, or 3 days).For example, a solution including stable non-covalently bound complexeswill often appear transparent whereas a solution including unstablenon-covalently bound complexes will appear translucent or cloudy.Further, it will be appreciated by those of ordinary skill in the art,that after a period of time, stable non-covalently bound complexes candisassociate and aggregate into their separate parts. Thus, a solutionincluding stable non-covalently bound complexes can become translucentor cloudy after a period of time (e.g., 6 hours, 12 hours, 24 hours, or3 days).

In vitro studies showed that Docetaxel is about 94% protein bound,mainly to al-acid glycoprotein, albumin, and lipoproteins. In threecancer patients, the in vitro binding to plasma proteins was found to beapproximately 97%. See Docetaxel Prescribing Information.

As used herein, the term “essentially fatty acid free” refers toproteins (e.g. serum albumin) that contain less than about 0.02% fattyacid by weight. For example, human serum albumin that is essentiallyfatty acid free can contain less than 0.02% fatty acid by weight.

As used herein, the term “fatty acids” refers to non-esterified fattyacids (e.g. linoleic acid, α-linoleic acid, γ-linoleic acid).

As used herein the term Docetaxel is a compound that has the CAS No.114977-28-5 and the following chemical structure:

Docetaxel is a white to almost-white powder. It is highly lipophilic andpractically insoluble in water.

Further, Docetaxel is a microtubule inhibitor indicated for breastcancer, non-small cell lung cancer, hormone refractory prostate cancer,gastric adenocarcinoma, and squamous cell carcinoma of the head and neckcancer.

In some embodiments, the Docetaxel can be a pharmaceutically acceptablesalt of Docetaxel.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the desired biological activity of the subjectcompound and exhibit minimal undesired toxicological effects. Thesepharmaceutically acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively. In some embodiments,pharmaceutically acceptable salts may be preferred over the respectivefree base or free acid because such salts impart greater stability orsolubility to the molecule thereby facilitating formulation into adosage form. Basic compounds are generally capable of formingpharmaceutically acceptable acid addition salts by treatment with asuitable acid. Suitable acids include pharmaceutically acceptableinorganic acids and pharmaceutically acceptable organic acids.Representative pharmaceutically acceptable acid addition salts includehydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate,sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate,propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate,acrylate, fumarate, malate, tartrate, citrate, salicylate,p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate,succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate,formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate,malonate, laurate, glutarate, glutamate, estolate, methanesulfonate(mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate,benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate(tosylate), napthalene-2-sulfonate, ethanedisulfonate, hydrogenbisulfide, bitartrate, gluconate, glucuronate,para-bromophenylsulfonate, carbonate, pyrosulfate, sulfite, bisulfite,monohydrogen phosphate, dihydrogen phosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, decanoate, caprylate, caprate,propiolate, suberate, sebacate, butyne-1,4-dioate, hexyne-1,6-dioate,terephthalate, sulfonate, xylenesulfonate, phenylpropionate,phenylbutyrate, β-hydroxybutyrate, glycolate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate and2,5-dihydroxybenzoate. Suitable bases include pharmaceuticallyacceptable inorganic bases and pharmaceutically acceptable organicbases. Representative pharmaceutically acceptable base addition saltsinclude hydroxide of alkali metals including sodium, potassium, andlithium; hydroxides of alkaline earth metals such as calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia, organic amines such as unsubstituted or hydroxyl-substitutedmono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine;pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-,bis-, or tris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like.

In some embodiments, the Docetaxel can be a Docetaxel with 1, 2, or 3equivalents of the water solvate. In some embodiments, the Docetaxel canbe a Docetaxel with three equivalents of the water solvate. In someembodiments, Docetaxel is the docetaxel trihydrate. In some embodiments,Docetaxel is the docetaxel monohydrate. In some embodiments, Docetaxelis the docetaxel anhydrous. In some embodiments, the docetaxel can be adocetaxel with one equivalent of the acetone solvate. In someembodiments, the docetaxel can be any one of docetaxel solvatesdisclosed, for example, in WO2010091650 or US2012007167, the disclosuresof which are incorporated herein by reference in its entirety.

In some embodiments, docetaxel is crystalline. In some embodiments,docetaxel is any one of the crystalline forms disclosed, for example, inWO2012115402, U.S. Pat. No. 8,410,294, US20100197944, US20100099897,U.S. Pat. No. 8,357,811, US20100160653, or US20070142457, thedisclosures of which are incorporated herein by reference in theirentirety.

In some embodiments, docetaxel in amorphous. In some embodiments.Docetaxel is any one of the amorphous forms disclosed, for example, inWO2008102374, the disclosure of which is incorporated herein byreference in its entirety.

Also, provided herein is a non-covalently bound complex includingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin are in a molar ratio from about 0.1:1 to about 5:1.

In some embodiments, the present disclosure provides a non-covalentlybound complex comprising Docetaxel and human serum albumin, wherein themolar ratio of Docetaxel and the human serum albumin in the complex isfrom about 0.1:1 to about 5:1.

In some embodiments, the Docetaxel and the human serum albumin have amolar ratio from about 0.1:1 to about 3:1, from about 0.5:1 to about2:1, from about 0.75:1 to about 1.5:1, or from about 0.8:1 to about1.3:1. In some embodiments, the Docetaxel and the human serum albuminhave a molar ratio of about 0.5:1, about 0.6:1, about 0.7:1, about0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1,about 1.4:1, or about 1.5:1.

In some embodiments, the molar ratio of Docetaxel and the human serumalbumin in the complex is from about 0.1:1 to about 3:1, from about0.5:1 to about 2:1, from about 0.75:1 to about 1.5:1, or from about0.8:1 to about 1.3:1 In some embodiments, the molar ratio of Docetaxeland the human serum albumin in the complex is about 0.5:1, about 0.6:1,about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about1.2:1, about 1.3:1, about 1.4:1, or about 1.5:1.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free. In some embodiments, thehuman serum albumin contains no more than two moles of fatty acids boundto one mole of human serum albumin. In some embodiments, the human serumalbumin contains no more than one mole of fatty acids bound to one moleof human serum albumin. In some embodiments, human serum albumincontains no more than 0.5 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.1 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.05 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.01 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.001 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0005 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0001 moles of fatty acids bound to one mole ofhuman serum albumin.

Also, provided herein is a composition comprising a non-covalently boundcomplex comprising Docetaxel and human serum albumin, wherein theDocetaxel and the human serum albumin in the composition have a molarratio from about 0.1:1 to about 5:1. In some embodiments, the presentdisclosure provides a composition comprising a non-covalently boundcomplex comprising Docetaxel and human serum albumin, wherein the molarratio of Docetaxel and the human serum albumin in the complex is fromabout 0.1:1 to about 5:1. In some embodiments, the pH of a compositioncomprising a non-covalently bound complex including Docetaxel and humanserum albumin is neutral (e.g., pH of the composition is from about 5 toabout 8, from about 5.5 to about 7.5, or from about 6 to about 7, or thepH of the composition is about 5, about 5.5, about 6, about 6.1, about6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8,about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about7.5, or about 8).

In some embodiments, the molar ratio of Docetaxel and the human serumalbumin is from about 0.1:1 to about 3:1, from about 0.5:1 to about 3:1,from about 0.5:1 to about 2:1, from about 0.75:1 to about 1.5:1, or fromabout 0.8:1 to about 1.3:1. In some embodiments, the molar ratio ofDocetaxel and the human serum albumin is about 0.2:1, about 0.3:1, about0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1,about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1,about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, or about 2.5:1.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free. In some embodiments, thehuman serum albumin contains no more than two moles of fatty acids boundto one mole of human serum albumin. In some embodiments, the human serumalbumin contains no more than one mole of fatty acids bound to one moleof human serum albumin. In some embodiments, human serum albumincontains no more than 0.5 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.1 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.05 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.01 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.001 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0005 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0001 moles of fatty acids bound to one mole ofhuman serum albumin.

In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution. In someembodiments, the aqueous solution is substantially free of solvent otherthan water. In some embodiments, the aqueous solution is free of solventother than water.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 0.1:1 to about 5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 0.1:1 to about 5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.2:1 to about 0.3:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.2:1 to about 0.3:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.1:1 to about 0.5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.1:1 to about 0.5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 0.1:1 to about 5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8, and wherein the clear aqueoussolution is substantially free of solvent other than water. In someembodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 0.1:1 to about 5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8, and wherein the clear aqueoussolution is free of solvent other than water.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.2:1 to about 0.3:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8, and wherein the clear aqueoussolution is substantially free of solvent other than water. In someembodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.2:1 to about 0.3:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8, and wherein the clear aqueoussolution is free of solvent other than water.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.1:1 to about 0.5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8, and wherein the clear aqueoussolution is substantially free of solvent other than water. In someembodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.1:1 to about 0.5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 5 to about 8, and wherein the clear aqueoussolution is free of solvent other than water.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 0.1:1 to about 5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5, and wherein the clear aqueoussolution is substantially free of solvent other than water. In someembodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 0.1:1 to about 5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5, and wherein the clear aqueoussolution is free of solvent other than water.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.2:1 to about 0.3:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5, and wherein the clear aqueoussolution is substantially free of solvent other than water. In someembodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.2:1 to about 0.3:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5, and wherein the clear aqueoussolution is free of solvent other than water.

In some embodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.1:1 to about 0.5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5, and wherein the clear aqueoussolution is substantially free of solvent other than water. In someembodiments, provided herein is a composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 1.1:1 to about 0.5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the clear aqueous solutionhas pH value from about 6 to about 7.5, and wherein the clear aqueoussolution is free of solvent other than water.

In some embodiments, the composition forms a clear aqueous solution,when the composition is dissolved in an aqueous solution, wherein theclear aqueous solution has pH value from about 5 to about 8. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 5.5 to about 7.8. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6.5 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6 to about 6.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6.5 to about 7. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 7 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value about 6, about 6.1, about 6.2, about 6.3,about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the composition is a clear aqueous solution for atleast 3 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 6 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 24 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 3 days when the composition is dissolved in an aqueous solution.In some embodiments, the aqueous solution is substantially free ofsolvent other than water. In some embodiments, the aqueous solution freeof solvent other than water.

Formulations suitable for parenteral administration include aqueous andnon-aqueous, isotonic sterile injection solutions, which can containanti-oxidants, buffers, bacteriostats, and solutes that render theformulation compatible with the blood of the intended recipient, andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.The formulations can be presented in unit-dose or multi-dose sealedcontainers, such as ampules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid excipient, for example, water, for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions can be prepared from sterile powders, granules, and tablets.

In some embodiments, the composition is a solid formulation. Forexample, the solid formulation can be produced in a uniform manner bylyophilization. A skilled artisan would recognize other methods, such asrotary evaporation, that can also produce solid formulations. In someembodiments, the pH of the solid formulation is neutral (e.g., pH of thecomposition is from about 5 to about 8, from about 5.5 to about 7.5, orfrom about 6 to about 7, or the pH od the composition is about 5, about5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the composition is an aqueous formulation. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water. In some embodiments, the aqueousformulation includes water and water-miscible organic solvents includingat least one of polyethylene glycol 300, polyethylene glycol 400,ethanol, methanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide. For example, thewater-miscible organic solvent can include ethanol. In some embodiments,the aqueous formulation includes water and ethanol. In some embodiments,the water-miscible organic solvent can be a mixture of water-miscibleorganic solvents. In some embodiments, the pH of the aqueous formulation(e.g., clear aqueous solution) is neutral (e.g., pH of the compositionis from about 5 to about 8, from about 5.5 to about 7.5, or from about 6to about 7, or the pH od the composition is about 5, about 5.5, about 6,about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3,about 7.4, about 7.5 or about 8).

As used herein, “substantially free of solvent,” in reference to anaqueous solution, refers to an aqueous solution that contains less than0.5%, by weight, of any non-water solvent. In some embodiments, theaqueous solution contains less than 0.1%, by weight, of any non-watersolvent. In some embodiments, the aqueous solution contains less than0.05%, by weight, of any non-water solvent.

In some embodiments, the aqueous formulation can be free of asurfactant. In some embodiments, the aqueous formulation can be free ofa surfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation can be substantially free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation can be substantially free of asurfactant selected from the group consisting of CREMOPHOR® surfactantsand Polysorbate 80.

As used herein, the term “substantially free of surfactant” refers to aformulation containing less than 0.0005%, less than 0.0003%, or lessthan 0.0001% of surfactants and/or less than 0.0005%, less than 0.0003%,or less than 0.0001% of surfactant.

In some embodiments, the aqueous formulation is a clear aqueoussolution. For example, the formulation can be a clear and stable aqueoussolution reconstituted from a sterile lyophilized powder. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation is substantially free of solvent otherthan water. In some embodiments, the aqueous formulation is a clearaqueous solution, wherein the aqueous formulation is free of solventother than water.

As used herein, the term “clear aqueous solution” refers to a solutioncontaining Docetaxel and HSA in a water containing solution that istransparent upon visual observation and essentially free of visibleparticles or precipitation of undissolved Docetaxel.

The term “essentially free of visible particles or precipitation ofundissolved Docetaxel” can be assessed as follows: after a clear aqueoussolution is filtered with a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 95% of the total amount ofDocetaxel in the aqueous solution before filtration. The total amount ofDocetaxel in the aqueous solution before filtration includes theparticles or precipitation of undissolved Docetaxel in the aqueoussolution or with the aqueous solution. The amount of the Docetaxel in anaqueous solution can be measured by the methods using HPLC. The methodsof measuring the amount of the Docetaxel in an aqueous solution areillustrated in the experimental examples described herein. The methodsare commonly understood by one of ordinary skill in the art to whichthis disclosure belongs.

When visually observed, for example, the term “clear aqueous solution”excludes a milky aqueous solution. Further, the term “clear aqueoussolution” excludes a cloudy or hazy aqueous solution.

As used herein, the term “micron” refers to a unit of measure of oneone-thousandth of a millimeter. In some embodiments, the term “micron”refers to a micrometer.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline solution. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 5% Dextrose water solution.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the aqueous formulation has pH value fromabout 5 to about 8. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline solution, wherein theaqueous formulation has pH value from about 5 to about 8. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 5% Dextrose water solution, wherein the aqueous formulationhas pH value from about 5 to about 8.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 5 to about 8. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 5 to about 8. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinthe pH of 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 5 to about 8. In some aspects of theaforementioned embodiments, the concentration of the reconstituted solidin the aqueous formulation is about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 150 mg or 200 mg per 1 ml of the aqueous solvent. Insome aspects of the aforementioned embodiments, the concentration of thereconstituted solid in the aqueous formulation is from about 10 mg per 1ml to about 500 mg per 1 ml of the aqueous solvent. In some aspects ofthe aforementioned embodiments, the concentration of the reconstitutedsolid in the aqueous formulation is from about 25 mg per 1 ml to about250 mg per 1 ml of the aqueous solvent. In some aspects of theaforementioned embodiments, the concentration of the reconstituted solidin the aqueous formulation is from about 30 mg per 1 ml to about 200 mgper 1 ml of the aqueous solvent. In some aspects of the aforementionedembodiments, the concentration of the reconstituted solid in the aqueousformulation is from about 40 mg per 1 ml to about 150 mg per 1 ml of theaqueous solvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 50 mg per 1 ml to about 125 mg per 1 ml of the aqueoussolvent.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 5 to about 8. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 6.7 to about 7.1. In some embodiments, the aqueous formulation isa clear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinthe pH of 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 6.7 to about 7.1. In some aspects ofthe aforementioned embodiments, the concentration of the reconstitutedsolid in the aqueous formulation is about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg or 200 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 10 mg per 1 ml to about 500 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 25 mg per 1 ml to about 250 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 30 mg per 1 ml to about 200 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 40 mg per 1 ml to about 150 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 50 mg per 1 ml to about 125 mg per 1 ml of the aqueoussolvent.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the aqueous formulation has pH value fromabout 6 to about 7.5. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline solution, wherein theaqueous formulation has pH value from about 6 to about 7.5. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 5% Dextrose water solution, wherein the aqueous formulationhas pH value from about 6 to about 7.5.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 6 to about 7.5. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 6 to about 7.5. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinpH of the 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 6 to about 7.5.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value of about 6, about 6.1, about 6.2, about6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9,about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, orabout 8. In some embodiments, the aqueous formulation is a clear aqueoussolution reconstituted from the solid formulation (e.g. the sterilelyophilized powder) in 0.9% saline solution, wherein the pH of 0.9%saline solution is about 5.4, and wherein the aqueous formulation has pHvalue of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments,the aqueous formulation is a clear aqueous solution reconstituted fromthe solid formulation (e.g. the sterile lyophilized powder) in 5%dextrose water solution, wherein pH of the 5% dextrose solution is about4.4, and wherein the aqueous formulation has pH value of about 6, about6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7,about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about7.4, about 7.5, or about 8.

In some embodiments, the aqueous formulation has pH value from about 5to about 8. In some embodiments, the aqueous formulation has pH valuefrom about 5.5 to about 7.8. In some embodiments, the aqueousformulation has pH value from about 6 to about 7.5. In some embodiments,the aqueous formulation has pH value from about 6.5 to about 7.5. Insome embodiments, the aqueous formulation has pH value from about 6 toabout 6.5. In some embodiments, the aqueous formulation has pH valuefrom about 6.5 to about 7. In some embodiments, the aqueous formulationhas pH value from about 7 to about 7.5. In some embodiments, the aqueousformulation has pH value about 6, about 6.1, about 6.2, about 6.3, about6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0,about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 5 toabout 8, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 5 to about 8, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 5.5 to about 7.8, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 5.5 to about7.8, and wherein the aqueous formulation is free of solvent other thanwater. In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 6 toabout 7.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 6 to about 7.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 6.5 to about 7.5, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 6.5 to about7.5, and wherein the aqueous formulation is free of solvent other thanwater. In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 6 toabout 6.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 6 to about 6.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 6.5 to about 7, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 6.5 to about 7,and wherein the aqueous formulation is free of solvent other than water.In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 7 toabout 7.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 7 to about 7.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value about 6, about 6.1, about 6.2, about 6.3, about 6.4, about6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1,about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value about 6, about 6.1, about6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8,about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, orabout 7.5, and wherein the aqueous formulation is free of solvent otherthan water.

In some embodiments, after a clear aqueous solution is filtered by a0.22 micron filter, the amount of Docetaxel in the filtered aqueoussolution is at least 96% of the total amount of Docetaxel in the aqueoussolution before filtration. In some embodiments, after a clear aqueoussolution is filtered by a 0.22 micron filter, the amount of Docetaxel inthe filtered aqueous solution is at least 97% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after a clear aqueous solution is filtered by a 0.22 micronfilter, the amount of Docetaxel in the filtered aqueous solution is atleast 98% of the total amount of Docetaxel in the aqueous solutionbefore filtration. In some embodiments, after a clear aqueous solutionis filtered by a 0.22 micron filter, the amount of Docetaxel in thefiltered aqueous solution is at least 99% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after a clear aqueous solution is filtered by a 0.22 micronfilter, the amount of Docetaxel in the filtered aqueous solution is atleast 99.5% of the total amount of Docetaxel in the aqueous solutionbefore filtration. In some embodiments, the aqueous formulation issubstantially free of solvent other than water.

In some embodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or99.5% of the total amount of Docetaxel in the aqueous solution beforefiltration, wherein the clear aqueous solution has pH value from about 5to about 8, and wherein the clear aqueous solution is substantially freeof solvent other than water. In some embodiments, after the aqueousformulation (e.g. a clear aqueous solution) is filtered by a 0.22 micronfilter, the amount of Docetaxel in the filtered aqueous solution is atleast 96%, 97%, 98%, 99%, or 99.5% of the total amount of Docetaxel inthe aqueous solution before filtration, wherein the clear aqueoussolution has pH value from about 6 to about 7.5, and wherein the clearaqueous solution is substantially free of solvent other than water. Insome embodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or99.5% of the total amount of Docetaxel in the aqueous solution beforefiltration, wherein the clear aqueous solution has pH value from about 5to about 8, and wherein the clear aqueous solution is free of solventother than water. In some embodiments, after the aqueous formulation(e.g. a clear aqueous solution) is filtered by a 0.22 micron filter, theamount of Docetaxel in the filtered aqueous solution is at least 96%,97%, 98%, 99%, or 99.5% of the total amount of Docetaxel in the aqueoussolution before filtration, wherein the clear aqueous solution has pHvalue from about 6 to about 7.5, and wherein the clear aqueous solutionis free of solvent other than water.

In some embodiments, the aqueous formulation is a clear aqueous solutionfor at least 3 hours at a temperature from about 1° C. to about 35° C.,about 1° C. to about 10° C., about 10° C. to about 20° C., about 20° C.to about 35° C., or about 1° C., about 5° C., about 10° C., about 15°C., about 20° C., about 25° C., about 30° C., or about 35° C. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 6 hours at a temperature from about 1° C. to about 35° C., about1° C. to about 10° C., about 10° C. to about 20° C., about 20° C. toabout 35° C., or about 1° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., or about 35° C. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 24 hours at a temperature from about 1° C. to about 35° C., about1° C. to about 10° C., about 10° C. to about 20° C., about 20° C. toabout 35° C., or about 1° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., or about 35° C. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 3 days at a temperature from about 1° C. to about 35° C., about 1°C. to about 10° C., about 10° C. to about 20° C., about 20° C. to about35° C., or about 1° C., about 5° C., about 10° C., about 15° C., about20° C., about 25° C., about 30° C., or about 35° C. In some embodiments,the aqueous formulation is substantially free of solvent other thanwater. In some embodiments, the aqueous formulation is free of solventother than water.

In some embodiments, the aqueous formulation is an aqueous solution,wherein after the aqueous solution is filtered by a 0.22 micron filter,the amount of Docetaxel in the filtered aqueous solution is at least 80%of the total amount of Docetaxel in the aqueous solution beforefiltration. In some embodiments, the aqueous formulation is an aqueoussolution, wherein after the aqueous solution is filtered by a 0.22micron filter, the amount of Docetaxel in the filtered aqueous solutionis at least 85% of the total amount of Docetaxel in the aqueous solutionbefore filtration. In some embodiments, the aqueous formulation is anaqueous solution, wherein after the aqueous solution is filtered by a0.22 micron filter, the amount of Docetaxel in the filtered aqueoussolution is at least 90% of the total amount of Docetaxel in the aqueoussolution before filtration.

Also, provided herein is a pharmaceutical composition comprising thecomposition comprising a non-covalently bound complex comprising theDocetaxel and the human serum albumin as described herein, and apharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition further comprises atleast one anti-cancer drug (e.g., any one of the anti-cancer drugs asdescribed herein).

As used herein, the term “pharmaceutically acceptable carrier” is meantany solution used to solubilize and deliver an agent to a subject. Adesirable pharmaceutically acceptable carrier is saline. Otherpharmaceutically acceptable carrier and their formulation are known toone skilled in the art and described, for example, in Remington'sPharmaceutical Sciences. (20^(th) edition), ed. A. Gennaro, 2003,Lippincon Williams & Wilkins.

Pharmaceutically acceptable carriers that may be used in thepharmaceutical compositions of the present application include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins (other than HSA), buffer substances such as phosphates,glycine, sorbic acid, potassium sorbate, salts or electrolytes, such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, and cellulose-based substances.

In some embodiments, the pharmaceutical composition is free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80.

In some embodiments, the pharmaceutical composition is substantiallyfree of a surfactant, such as CREMOPHOR® surfactants and Polysorbate 80.In some embodiments, the pharmaceutical composition is free of asurfactant selected from the group consisting of CREMOPHOR® surfactantsand Polysorbate 80.

Also, provided herein is a method of treating a proliferative diseasecomprising the step of administering to a subject in need thereof atherapeutically effective amount of a pharmaceutical composition asdescribed herein.

As used herein, the terms “individual”, “patient”, or “subject” are usedinterchangeably and refer to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the term “proliferative disease” refers to a diseasecaused by excessive proliferation of cells and turnover of cellularmatrix. Non-limiting examples of proliferative diseases include cancer,atherosclerosis, arthritis (e.g. rheumatoid arthritis), psoriasis,fibrosis (e.g. pulmonary fibrosis, idiopathic pulmonary fibrosis),scleroderma and cirrhosis (e.g. cirrhosis of the liver).

Also, provided herein is a method of treating a cancer, the methodcomprising the step of administering to a subject in need thereof of atherapeutically effective amount of a pharmaceutical compositioncomprising the composition comprising a non-covalently bound complexcomprising the Docetaxel and the human serum albumin as describedherein, and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, brain cancer, breast cancer, colorectal cancer, cervicalcancer, gastrointestinal cancer, genitourinary cancer, head and neckcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, skin cancer, and testicular cancer.

In some embodiments, cancer is selected from sarcoma, angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma,fibroma, lipoma, teratoma, non-small cell lung cancer (NSCLC),bronchogenic carcinoma squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma, alveolar bronchiolarcarcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoushamartoma, mesothelioma, gastrointestinal cancer, cancer of theesophagus, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,lymphoma, cancer of the stomach, carcinoma, lymphoma, leiomyosarcoma,cancer of the pancreas, ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumor, vipoma, cancer of the small bowel,adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma,hemangioma, lipoma, neurofibroma, fibroma, cancer of the large bowel orcolon, tubular adenoma, villous adenoma, hamartoma, leiomyoma,genitourinary tract cancer, cancer of the kidney adenocarcinoma, Wilm'stumor (nephroblastoma), lymphoma, leukemia, cancer of the bladder,cancer of the urethra, squamous cell carcinoma, transitional cellcarcinoma, cancer of the prostate, cancer of the testis, seminoma,teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma,sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoidtumors, lipoma, liver cancer, hepatoma hepatocellular carcinoma,cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma, bone cancer, osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,malignant giant cell tumor, chordoma, osteochrondroma(osteocartilaginous exostoses), benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma giant cell tumor, nervous systemcancer, cancer of the skull, osteoma, hemangioma, granuloma, xanthoma,osteitis deformans, cancer of the meninges meningioma, meningiosarcoma,gliomatosis, cancer of the brain, astrocytoma, medulloblastoma, glioma,ependymoma, germinoma (pinealoma), glioblastoma multiforme,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, cancerof the spinal cord, neurofibroma, meningioma, glioma, sarcoma,gynecological cancer, cancer of the uterus, endometrial carcinoma,cancer of the cervix, cervical carcinoma, pre tumor cervical dysplasia,cancer of the ovaries, ovarian carcinoma, serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecacell tumor, Sertoli Leydig cell tumor, dysgerminoma, malignant teratoma,cancer of the vulva, squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma, cancer of the vagina, clear cellcarcinoma, squamous cell carcinoma, botryoid sarcoma, embryonalrhabdomyosarcoma, cancer of the fallopian tubes, hematologic cancer,cancer of the blood, acute myeloid leukemia (AML), chronic myeloidleukemia (CML), acute lymphoblastic leukemia (ALL), chroniclymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome, Hodgkin'slymphoma, non-Hodgkin's lymphoma (malignant lymphoma), Waldenstrom'smacroglobulinemia, skin cancer, malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplasticnevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, adrenal glandcancer, and neuroblastoma.

As used herein, an “effective amount,” “therapeutically effectiveamount,” or a “pharmaceutically-effective amount” in reference to thecompounds or compositions of the instant invention refers to the amountsufficient to induce a desired biological, pharmacological, ortherapeutic outcome in a subject. That result can be reduction,mitigation, delay, shortening the time to resolution of, alleviation ofthe signs or symptoms of, or exert a medically-beneficial effect uponthe underlying pathophysiology or pathogenesis of an expected orobserved side-effect, toxicity, disorder or condition, or any otherdesired alteration of a biological system. In cancer treatment, theresult will generally include the reduction, mitigation, limitation,and/or, delay of the deleterious physiological manifestations, growth ormetastases of neoplasms.

In some embodiments, the cancer is a solid tumor cancer. In someembodiments, the cancer is selected from the group consisting of breastcancer, non-small cell lung cancer, prostate cancer, gastric cancer,head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi'ssarcoma. In some embodiments, the cancer is a breast cancer. In someembodiments, the cancer is a non-small cell lung cancer. In someembodiments, the cancer is a prostate cancer. In some embodiments, thecancer is a gastric cancer. In some embodiments, the cancer is a headand neck cancer. In some embodiments the cancer is an ovarian cancer. Insome embodiments, the cancer is a pancreatic cancer. In someembodiments, the cancer is a Kaposi's sarcoma.

In some embodiments, the method of treating cancer (e.g. any one ofcancers described herein) comprises the step of administering to asubject in need thereof of a therapeutically effective amount of acomposition comprising a non-covalently bound complex comprising theDocetaxel and the human serum albumin as described herein, and atherapeutically effective amount of at least one inhibitor of thefollowing kinases for the treatment of cancer: PIM, Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf.

In some embodiments, the method of treating cancer (e.g. any one ofcancers described herein) comprises the step of administering to asubject in need thereof of a therapeutically effective amount of apharmaceutical composition comprising the composition comprising anon-covalently bound complex comprising the Docetaxel and the humanserum albumin as described herein, and a therapeutically effectiveamount of at least one anti-cancer drug. Examples of an anti-cancer druginclude aberaterone, aberaterone acetate, abarelix, aldesleukin,alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole,arsenic trioxide, asparaginase, azacitidine, bavituximab, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, enzalutamide, epirubicin, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinibditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinostat and zoledronate.

In some embodiments, a composition comprising a non-covalently boundcomplex comprising the Docetaxel and the human serum albumin asdescribed herein and an anti-cancer drug are administeredsimultaneously.

In some embodiments, a composition comprising a non-covalently boundcomplex comprising the Docetaxel and the human serum albumin asdescribed herein and an anti-cancer drug are administered consecutively.

The composition comprising a non-covalently bound complex comprising theDocetaxel and the human serum albumin described herein can beadministered to an individual, such as human, via various routes, suchas parenterally, including intravenous, intra-arterial, intraperitoneal,intrapulmonary, oral, inhalation, intravesicular, intramuscular,intra-tracheal, subcutaneous, intraocular, intrathecal, or transdermal.For example, the composition can be administered by inhalation to treatconditions of the respiratory tract. The composition can be used totreat respiratory conditions such as pulmonary fibrosis, broncheolitisobliterans, lung cancer, bronchoalveolar carcinoma, and the like. Insome embodiments, the nanoparticle composition is administratedintravenously.

The methods described herein may be performed alone or in conjunctionwith another therapy, such as surgery, radiation, chemotherapy,immunotherapy, gene therapy, and the like. Additionally, a person havinga greater risk of developing the proliferative disease may receivetreatments to inhibit or and/or delay the development of the disease.

As will be understood by those of ordinary skill in the art, theappropriate doses of Docetaxel will be approximately those alreadyemployed in clinical therapies wherein Docetaxel is administered aloneor in combination with other chemotherapeutic agents. Variation indosage will likely occur depending on the condition being treated.Appropriate effective doses will also vary, as recognized by thoseskilled in the art, depending on the severity of the disease, the routeof administration, the sex, age and general health condition of thesubject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents, and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forDocetaxel.

Also, provided herein is a composition comprising Docetaxel and humanserum albumin, wherein the Docetaxel and the human serum albumin in thecomposition have a molar ratio from about 0.1:1 to about 5:1, whereinthe composition is a clear aqueous solution when the composition isdissolved in an aqueous solution, and wherein the composition has asolubility in an aqueous solution of at least 10 mg/ml. In some aspectsof these embodiments, pH of the composition is neutral (e.g., pH of thecomposition is from about 5 to about 8, from about 5.5 to about 7.5, orfrom about 6 to about 7, or the pH of the composition is about 5, about5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5, or about 8).

In some embodiments, the present disclosure provides a compositioncomprising Docetaxel and human serum albumin, wherein the molar ratio ofDocetaxel and the human serum albumin in the composition is from about0.1:1 to about 5:1, wherein the composition forms a clear aqueoussolution when the composition is dissolved in an aqueous solution, andwherein the solubility of the composition in the aqueous solution is atleast 10 mg/ml. In some aspects of these embodiments, pH of thecomposition is neutral (e.g., pH of the composition is from about 5 toabout 8, from about 5.5 to about 7.5, or from about 6 to about 7, or thepH of the composition is about 5, about 5.5, about 6, about 6.1, about6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8,about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about7.5, or about 8).

In some embodiments, the composition has a solubility in an aqueoussolution of about 10 mg/ml, about 20 mg/ml, about 30 mg/ml, about 40mg/ml, about 50 mg/ml, 60 mg/ml, about 70 mg/ml, about 80 mg/ml, about90 mg/ml, about 100 mg/ml, about 110 mg/ml, about 120 mg/ml, about 130mg/ml, about 140 mg/ml, about 150 mg/ml, or about 200 mg/ml.

In some embodiments, the solubility of the composition in an aqueoussolution is at least about 10 mg/ml, at least about 20 mg/ml, at leastabout 30 mg/ml, at least about at least 40 mg/ml, at least about 50mg/ml, at least 60 mg/ml, at least about 70 mg/ml, at least about 80mg/ml, at least about 90 mg/ml, at least about 100 mg/ml, at least about150 mg/ml, or at least about 200 mg/ml.

As used herein, the term “aqueous solution” refers to a solution,wherein at least one solvent is water and the weight % of water in themixture of solvents is at least 50%, at least 60%, at least 70% or atleast 90%. In some embodiments, aqueous solution is a solution in whichwater is the only solvent. In some embodiments, aqueous solution is abuffer (e.g., phosphate buffer or a carbonate buffer). In someembodiments, the buffer is physiological buffer or a pharmaceuticallyacceptable buffer. In some embodiments, the buffer is any one of buffersdescribed, for example, in Y.-C. Lee et al. International Journal ofPharmaceutics 253 (2003) 111-119, the disclosure of which isincorporated herein by reference in its entirety. In some embodiments,the buffer comprises maleic acid, tartaric acid, lactic acid, citricacid, acetic acid, sodium bicarbonate, sodium phosphate, or mixturesthereof. In some embodiments, the pH range of the buffer is from about 3to about 9, from about 4 to about 8, from about 5 to about 7, from about6 to about 7, from about 3 to about 5, from about 3 to about 7, fromabout 4 to about 6, or from about 6 to about 6. In some embodiments, thepH of the buffer is about 4, about 5, about 6, about 6.4, about 6.5,about 6.6, about 7, about 7.5, or about 8. In other embodiments, aqueoussolution is 0.9% saline (wherein the pH of 0.9% saline is from about 4to about 6, from about 4.5 to about 6, or from about 5 to about 6, orwherein the pH of 0.9% saline is about 5, about 5.2, about 5.4, about5.5, or about 6). In yet other embodiments, aqueous solution is 5%dextrose solution (wherein the pH of 5% dextrose solution is from about3 to about 5, from about 3.5 to about 5, or from about 4 to about 5, orwherein the pH of 5% dextrose solution is about 4, about 4.2, about 4.4,about 4.5, or about 5).

As used herein, the term “aqueous solvent” refers to a liquid comprisingat least 50%, at least 60%, at least 70%, at least 90% or at least 95%water. In some embodiments, aqueous solvent is water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 0.1:1 toabout 5:1, wherein the composition is a clear aqueous solution when thecomposition is dissolved in an aqueous solution, and wherein the clearaqueous solution has pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 0.1:1 toabout 5:1, wherein the composition is a clear aqueous solution when thecomposition is dissolved in an aqueous solution, and wherein the clearaqueous solution has pH value from about 5 to about 8, and wherein theclear aqueous solution is substantially free of solvent other thanwater. In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 0.1:1 toabout 5:1, wherein the composition is a clear aqueous solution when thecomposition is dissolved in an aqueous solution, and wherein the clearaqueous solution has pH value from about 5 to about 8, and wherein theclear aqueous solution is free of solvent other than water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 0.1:1 toabout 5:1, wherein the composition is a clear aqueous solution when thecomposition is dissolved in an aqueous solution, and wherein the clearaqueous solution has pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 0.1:1 toabout 5:1, wherein the composition is a clear aqueous solution when thecomposition is dissolved in an aqueous solution, and wherein the clearaqueous solution has pH value from about 6 to about 7.5, and wherein theclear aqueous solution is substantially free of solvent other thanwater. In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 0.1:1 toabout 5:1, wherein the composition is a clear aqueous solution when thecomposition is dissolved in an aqueous solution, and wherein the clearaqueous solution has pH value from about 6 to about 7.5, and wherein theclear aqueous solution is free of solvent other than water.

In some embodiments, the Docetaxel and the human serum albumin have amolar ratio in the composition from about 0.1:1 to about 3:1, from about0.2:1 to about 3:1, from about 0.2:1 to about 2:1, from about 0.5:1 toabout 2:1, from about 0.75:1 to about 1.5:1, or from about 0.8:1 toabout 1.3:1. In some embodiments, the Docetaxel and the human serumalbumin have a molar ratio in the composition of about 0.2:1, about0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1,about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1,about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, or about2.5:1.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free. In some embodiments, thehuman serum albumin contains no more than two moles of fatty acids boundto one mole of human serum albumin. In some embodiments, the human serumalbumin contains no more than one mole of fatty acids bound to one moleof human serum albumin. In some embodiments, human serum albumincontains no more than 0.5 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.1 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.05 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.01 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.001 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0005 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0001 moles of fatty acids bound to one mole ofhuman serum albumin.

In some embodiments, the Docetaxel can be a pharmaceutically acceptablesalt of Docetaxel. In some embodiments, the Docetaxel can be a Docetaxelwith three equivalents of the water solvate. In some embodiments,Docetaxel can be any one of crystal forms, amorphous forms, solvates andhydrates as described herein.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.2:1 toabout 0.3:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.2:1 toabout 0.3:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is substantially free of solvent other thanwater. In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.2:1 toabout 0.3:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is free of solvent other than water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.2:1 toabout 0.3:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.2:1 toabout 0.3:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 6 to about 7.5, andwherein the clear aqueous solution is substantially free of solventother than water. In some embodiments, provided herein is a compositioncomprising Docetaxel and human serum albumin, wherein the Docetaxel andthe human serum albumin in the composition have a molar ratio from about1.2:1 to about 0.3:1, wherein the composition is a clear aqueoussolution when the composition is dissolved in an aqueous solution, andwherein the clear aqueous solution has pH value from about 6 to about7.5, and wherein the clear aqueous solution is free of solvent otherthan water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.1:1 toabout 0.5:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.1:1 toabout 0.5:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is substantially free of solvent other thanwater. In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.1:1 toabout 0.5:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is free of solvent other than water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.1:1 toabout 0.5:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a molar ratio from about 1.1:1 toabout 0.5:1, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 6 to about 7.5, andwherein the clear aqueous solution is substantially free of solventother than water. In some embodiments, provided herein is a compositioncomprising Docetaxel and human serum albumin, wherein the Docetaxel andthe human serum albumin in the composition have a molar ratio from about1.1:1 to about 0.5:1, wherein the composition is a clear aqueoussolution when the composition is dissolved in an aqueous solution, andwherein the clear aqueous solution has pH value from about 6 to about7.5, and wherein the clear aqueous solution is free of solvent otherthan water.

In some embodiments, the composition forms a clear aqueous solution,when the composition is dissolved in an aqueous solution, wherein theclear aqueous solution has pH value from about 5 to about 8. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 5.5 to about 7.8. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6.5 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6 to about 6.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6.5 to about 7. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 7 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value about 6, about 6.1, about 6.2, about 6.3,about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, wherein after theclear aqueous solution is filtered by a 0.22 micron filter, the amountof Docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%,99%, or 99.5% of the total amount of Docetaxel in the aqueous solutionbefore the filtration, wherein the clear aqueous solution has pH valuefrom about 5 to about 8, and wherein the clear aqueous solution issubstantially free of solvent other than water. In some embodiments, thecomposition is a clear aqueous solution when the composition isdissolved in an aqueous solution, wherein after the clear aqueoussolution is filtered by a 0.22 micron filter, the amount of Docetaxel inthe filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5%of the total amount of Docetaxel in the aqueous solution before thefiltration, wherein the clear aqueous solution has pH value from about 6to about 7.5, and wherein the clear aqueous solution is substantiallyfree of solvent other than water. In some embodiments, the compositionis a clear aqueous solution when the composition is dissolved in anaqueous solution, wherein after the clear aqueous solution is filteredby a 0.22 micron filter, the amount of Docetaxel in the filtered aqueoussolution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount ofDocetaxel in the aqueous solution before the filtration, wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is free of solvent other than water. In someembodiments, the composition is a clear aqueous solution when thecomposition is dissolved in an aqueous solution, wherein after the clearaqueous solution is filtered by a 0.22 micron filter, the amount ofDocetaxel in the filtered aqueous solution is at least 96%, 97%, 98%,99%, or 99.5% of the total amount of Docetaxel in the aqueous solutionbefore the filtration, wherein the clear aqueous solution has pH valuefrom about 6 to about 7.5, and wherein the clear aqueous solution isfree of solvent other than water.

In some embodiments, the composition forms a clear aqueous solution forat least 6 hours when the composition is dissolved in an aqueoussolution. In some embodiments, the composition forms a clear aqueoussolution for at least 24 hours when the composition is dissolved in anaqueous solution. In some embodiments, the composition forms a clearaqueous solution for at least 3 days when the composition is dissolvedin an aqueous solution. In some embodiments, the aqueous solution issubstantially free of solvent other than water. In some embodiments, theaqueous solution is free of solvent other than water.

In some embodiments, the composition is a solid formulation. Forexample, the solid formulation can be produced in a uniform manner bylyophilization. A skilled artisan would recognize other methods, such asrotary evaporation, that can also produce solid formulations.

In some embodiments, the composition is an aqueous formulation. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water. In some embodiments, the aqueousformulation includes water and water-miscible organic solvents includingat least one of polyethylene glycol 300, polyethylene glycol 400,ethanol, methanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide. For example, thewater-miscible organic solvent can include ethanol. In some embodiments,the aqueous formulation includes water and ethanol. In some embodiments,the water-miscible organic solvent can be a mixture of water-miscibleorganic solvents.

In some embodiments, the aqueous formulation can be free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation can be substantially free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation can be substantially free of asurfactant selected from the group consisting of CREMOPHOR® surfactantsand Polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueoussolution. For example, the formulation can be a clear and stable aqueoussolution reconstituted from a sterile lyophilized powder. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation is substantially free of solvent otherthan water. In some embodiments, the aqueous formulation is a clearaqueous solution, wherein the aqueous formulation is free of solventother than water.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline. In some embodiments, theaqueous formulation is a clear aqueous solution reconstituted from thesolid formulation (e.g. the sterile lyophilized powder) in 5% Dextrosesolution.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the aqueous formulation has pH value fromabout 5 to about 8. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline, wherein the aqueousformulation has pH value from about 5 to about 8. In some embodiments,the aqueous formulation is a clear aqueous solution reconstituted fromthe solid formulation (e.g. the sterile lyophilized powder) in 5%Dextrose solution, wherein the aqueous formulation has pH value fromabout 5 to about 8.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 5 to about 8. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 5 to about 8. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinthe pH of 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 5 to about 8. In some aspects of theaforementioned embodiments, the concentration of the reconstituted solidin the aqueous formulation is about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 150 mg or 200 mg per 1 ml of the aqueous solvent. Insome aspects of the aforementioned embodiments, the concentration of thereconstituted solid in the aqueous formulation is from about 10 mg per 1ml to about 500 mg per 1 ml of the aqueous solvent. In some aspects ofthe aforementioned embodiments, the concentration of the reconstitutedsolid in the aqueous formulation is from about 25 mg per 1 ml to about250 mg per 1 ml of the aqueous solvent. In some aspects of theaforementioned embodiments, the concentration of the reconstituted solidin the aqueous formulation is from about 30 mg per 1 ml to about 200 mgper 1 ml of the aqueous solvent. In some aspects of the aforementionedembodiments, the concentration of the reconstituted solid in the aqueousformulation is from about 40 mg per 1 ml to about 150 mg per 1 ml of theaqueous solvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 50 mg per 1 ml to about 125 mg per 1 ml of the aqueoussolvent.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 5 to about 8. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 6.7 to about 7.1. In some embodiments, the aqueous formulation isa clear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinthe pH of 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 6.7 to about 7.1. In some aspects ofthe aforementioned embodiments, the concentration of the reconstitutedsolid in the aqueous formulation is about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg or 200 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 10 mg per 1 ml to about 500 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 25 mg per 1 ml to about 250 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 30 mg per 1 ml to about 200 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 40 mg per 1 ml to about 150 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 50 mg per 1 ml to about 125 mg per 1 ml of the aqueoussolvent.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the aqueous formulation has pH value fromabout 6 to about 7.5. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline, wherein the aqueousformulation has pH value from about 6 to about 7.5. In some embodiments,the aqueous formulation is a clear aqueous solution reconstituted fromthe solid formulation (e.g. the sterile lyophilized powder) in 5%Dextrose solution, wherein the aqueous formulation has pH value fromabout 6 to about 7.5.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 6 to about 7.5. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 6 to about 7.5. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinpH of the 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 6 to about 7.5.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value of about 6, about 6.1, about 6.2, about6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9,about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, orabout 8. In some embodiments, the aqueous formulation is a clear aqueoussolution reconstituted from the solid formulation (e.g. the sterilelyophilized powder) in 0.9% saline solution, wherein the pH of 0.9%saline solution is about 5.4, and wherein the aqueous formulation has pHvalue of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments,the aqueous formulation is a clear aqueous solution reconstituted fromthe solid formulation (e.g. the sterile lyophilized powder) in 5%dextrose water solution, wherein pH of the 5% dextrose solution is about4.4, and wherein the aqueous formulation has pH value of about 6, about6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7,about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about7.4, about 7.5, or about 8.

In some embodiments, the aqueous formulation has pH value from about 5to about 8. In some embodiments, the aqueous formulation has pH valuefrom about 5.5 to about 7.8. In some embodiments, the aqueousformulation has pH value from about 6 to about 7.5. In some embodiments,the aqueous formulation has pH value from about 6.5 to about 7.5. Insome embodiments, the aqueous formulation has pH value from about 6 toabout 6.5. In some embodiments, the aqueous formulation has pH valuefrom about 6.5 to about 7. In some embodiments, the aqueous formulationhas pH value from about 7 to about 7.5. In some embodiments, the aqueousformulation has pH value about 6, about 6.1, about 6.2, about 6.3, about6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0,about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 5 toabout 8, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 5 to about 8, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 5.5 to about 7.8, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 5.5 to about7.8, and wherein the aqueous formulation is free of solvent other thanwater. In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 6 toabout 7.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 6 to about 7.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 6.5 to about 7.5, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 6.5 to about7.5, and wherein the aqueous formulation is free of solvent other thanwater. In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 6 toabout 6.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 6 to about 6.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 6.5 to about 7, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 6.5 to about 7,and wherein the aqueous formulation is free of solvent other than water.In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 7 toabout 7.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 7 to about 7.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value about 6, about 6.1, about 6.2, about 6.3, about 6.4, about6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1,about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value about 6, about 6.1, about6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8,about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, orabout 7.5, and wherein the aqueous formulation is free of solvent otherthan water.

In some embodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 96% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 97% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 98% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 99% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 99.5% of the total amountof Docetaxel in the aqueous solution before filtration. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or99.5% of the total amount of Docetaxel in the aqueous solution beforefiltration, wherein the clear aqueous solution has pH value from about 5to about 8, and wherein the clear aqueous solution is substantially freeof solvent other than water. In some embodiments, after the aqueousformulation (e.g. a clear aqueous solution) is filtered by a 0.22 micronfilter, the amount of Docetaxel in the filtered aqueous solution is atleast 96%, 97%, 98%, 99%, or 99.5% of the total amount of Docetaxel inthe aqueous solution before filtration, wherein the clear aqueoussolution has pH value from about 6 to about 7.5, and wherein the clearaqueous solution is substantially free of solvent other than water. Insome embodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or99.5% of the total amount of Docetaxel in the aqueous solution beforefiltration, wherein the clear aqueous solution has pH value from about 5to about 8, and wherein the clear aqueous solution is free of solventother than water. In some embodiments, after the aqueous formulation(e.g. a clear aqueous solution) is filtered by a 0.22 micron filter, theamount of Docetaxel in the filtered aqueous solution is at least 96%,97%, 98%, 99%, or 99.5% of the total amount of Docetaxel in the aqueoussolution before filtration, wherein the clear aqueous solution has pHvalue from about 6 to about 7.5, and wherein the clear aqueous solutionis free of solvent other than water.

In some embodiments, the aqueous formulation is a clear aqueous solutionfor at least 3 hours at a temperature from about 1° C. to about 35° C.,about 1° C. to about 10° C., about 10° C. to about 20° C., about 20° C.to about 35° C., or about 1° C., about 5° C., about 10° C., about 15°C., about 20° C., about 25° C., about 30° C., or about 35° C. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 6 hours at a temperature from about 1° C. to about 35° C., about1° C. to about 10° C., about 10° C. to about 20° C., about 20° C. toabout 35° C., or about 1° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., or about 35° C. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 24 hours at a temperature from about 1° C. to about 35° C., about1° C. to about 10° C., about 10° C. to about 20° C., about 20° C. toabout 35° C., or about 1° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., or about 35° C. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 3 days at a temperature from about 1° C. to about 35° C., about 1°C. to about 10° C., about 10° C. to about 20° C., about 20° C. to about35° C., or about 1° C., about 5° C., about 10° C., about 15° C., about20° C., about 25° C., about 30° C., or about 35° C. In some embodiments,the aqueous formulation is substantially free of solvent other thanwater. In some embodiments, the aqueous formulation is free of solventother than water.

Also, provided herein is a pharmaceutical composition comprising thecomposition comprising the Docetaxel and the human serum albumin asdescribed herein, and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80.

In some embodiments, the pharmaceutical composition is substantiallyfree of a surfactant, such as CREMOPHOR® surfactants and Polysorbate 80.

Also, provided herein is a method of treating a proliferative diseasecomprising the step of administering to a subject in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprising the composition comprising the Docetaxel and the human serumalbumin as described herein, and a pharmaceutically acceptable carrier.

Also, provided herein is a method of treating a cancer, the methodcomprising the step of administering to a subject in need thereof of atherapeutically effective amount of a pharmaceutical compositioncomprising the composition comprising the Docetaxel and the human serumalbumin as described herein, and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is any one of cancers described herein.

In some embodiments, the cancer is a solid tumor cancer. In someembodiments, the cancer is selected from the group consisting of breastcancer, non-small cell lung cancer, prostate cancer, gastric cancer,head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi'ssarcoma. In some embodiments, the cancer is a breast cancer. In someembodiments, the cancer is a non-small cell lung cancer. In someembodiments, the cancer is a prostate cancer. In some embodiments, thecancer is a gastric cancer. In some embodiments, the cancer is a headand neck cancer. In some embodiments the cancer is an ovarian cancer. Insome embodiments, the cancer is a pancreatic cancer. In someembodiments, the cancer is a Kaposi's sarcoma.

In some embodiments, the method of treating cancer (e.g. any one ofcancers described herein) comprises the step of administering to asubject in need thereof a therapeutically effective amount of apharmaceutical composition comprising the composition comprising theDocetaxel and the human serum albumin as described herein and atherapeutically effective amount of at least one inhibitor of thekinases for the treatment of cancer described herein.

In some embodiments, the method of treating cancer (e.g. any one ofcancers described herein) comprises the step of administering to asubject in need thereof a therapeutically effective amount of apharmaceutical composition comprising the composition comprising theDocetaxel and the human serum albumin as described herein and atherapeutically effective amount of at least one anti-cancer drugdescribed herein.

In some embodiments, a composition comprising the Docetaxel and thehuman serum albumin as described herein and an anti-cancer drug areadministered simultaneously.

In some embodiments, a composition comprising the Docetaxel and thehuman serum albumin as described herein and an anti-cancer drug areadministered consecutively.

The composition comprising the Docetaxel and the human serum albumindescribed herein can be administered to an individual, such as human,via various routes, such as parenterally, including intravenous,intra-arterial, intraperitoneal, intrapulmonary, oral, inhalation,intravesicular, intramuscular, intra-tracheal, subcutaneous,intraocular, intrathecal, or transdermal. For example, the compositioncan be administered by inhalation to treat conditions of the respiratorytract. The composition can be used to treat respiratory conditions suchas pulmonary fibrosis, broncheolitis obliterans, lung cancer,bronchoalveolar carcinoma, and the like. In some embodiments, thenanoparticle composition is administrated intravenously.

The methods described herein may be performed alone or in conjunctionwith another therapy, such as surgery, radiation, chemotherapy,immunotherapy, gene therapy, and the like. Additionally, a person havinga greater risk of developing the proliferative disease may receivetreatments to inhibit or and/or delay the development of the disease.

As will be understood by those of ordinary skill in the art, theappropriate doses of Docetaxel will be approximately those alreadyemployed in clinical therapies wherein Docetaxel is administered aloneor in combination with other chemotherapeutic agents. Variation indosage will likely occur depending on the condition being treated.Appropriate effective doses will also vary, as recognized by thoseskilled in the art, depending on the severity of the disease, the routeof administration, the sex, age and general health condition of thesubject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents, and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forDocetaxel.

Also, provided herein is a composition comprising Docetaxel and humanserum albumin, wherein the Docetaxel and the human serum albumin in thecomposition have a ratio by weight from about 1:50 to about 1:1000. Insome embodiments, the pH of the composition is neutral (e.g., pH of thecomposition is from about 5 to about 8, from about 5.5 to about 7.5, orfrom about 6 to about 7, or the pH of the composition is about 5, about5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5, or about 8).

In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:50 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:60 to about 1:300. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:250. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:200. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:150. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:120. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:1000.In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight of about 1:60, about 1:70, about1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130,about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240,or about 1:250.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free. In some embodiments, thehuman serum albumin contains no more than two moles of fatty acids boundto one mole of human serum albumin. In some embodiments, the human serumalbumin contains no more than one mole of fatty acids bound to one moleof human serum albumin. In some embodiments, human serum albumincontains no more than 0.5 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.1 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.05 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.01 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.001 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0005 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0001 moles of fatty acids bound to one mole ofhuman serum albumin.

In some embodiments, the Docetaxel can be a pharmaceutically acceptablesalt of Docetaxel. In some embodiments, the Docetaxel can be a Docetaxelwith three equivalents of the water solvate. In some embodiments,Docetaxel can be any one of crystal forms, amorphous forms, solvates andhydrates as described herein.

In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution. In someembodiments, the aqueous solution is substantially free of solvent otherthan water. In some embodiments, the aqueous solution is free of solventother than water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:50to about 1:1000, wherein the composition is a clear aqueous solutionwhen the composition is dissolved in an aqueous solution, and whereinthe clear aqueous solution has pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:50to about 1:1000, wherein the composition is a clear aqueous solutionwhen the composition is dissolved in an aqueous solution, and whereinthe clear aqueous solution has pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:70to about 1:250, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:70to about 1:250, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:80to about 150, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:80to about 1:150, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 6 to about 7.5.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:50to about 1:1000, wherein the composition is a clear aqueous solutionwhen the composition is dissolved in an aqueous solution, and whereinthe clear aqueous solution has pH value from about 5 to about 8, andwherein the clear aqueous solution is substantially free of solventother than water. In some embodiments, provided herein is a compositioncomprising Docetaxel and human serum albumin, wherein the Docetaxel andthe human serum albumin in the composition have a ratio by weight fromabout 1:50 to about 1:1000, wherein the composition is a clear aqueoussolution when the composition is dissolved in an aqueous solution, andwherein the clear aqueous solution has pH value from about 5 to about 8,and wherein the clear aqueous solution is free of solvent other thanwater.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:70to about 1:250, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is substantially free of solvent other thanwater. In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:70to about 1:250, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is free of solvent other than water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:80to about 1:150, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is substantially free of solvent other thanwater. In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:80to about 1:150, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is free of solvent other than water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:50to about 1:1000, wherein the composition is a clear aqueous solutionwhen the composition is dissolved in an aqueous solution, and whereinthe clear aqueous solution has pH value from about 6 to about 7.5, andwherein the clear aqueous solution is substantially free of solventother than water. In some embodiments, provided herein is a compositioncomprising Docetaxel and human serum albumin, wherein the Docetaxel andthe human serum albumin in the composition have a ratio by weight fromabout 1:50 to about 1:1000, wherein the composition is a clear aqueoussolution when the composition is dissolved in an aqueous solution, andwherein the clear aqueous solution has pH value from about 6 to about7.5, and wherein the clear aqueous solution is free of solvent otherthan water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:70to about 1:250, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 6 to about 7.5, andwherein the clear aqueous solution is substantially free of solventother than water. In some embodiments, provided herein is a compositioncomprising Docetaxel and human serum albumin, wherein the Docetaxel andthe human serum albumin in the composition have a ratio by weight fromabout 1:70 to about 1:250, wherein the composition is a clear aqueoussolution when the composition is dissolved in an aqueous solution, andwherein the clear aqueous solution has pH value from about 6 to about7.5, and wherein the clear aqueous solution is free of solvent otherthan water.

In some embodiments, provided herein is a composition comprisingDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:80to about 1:150, wherein the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, and wherein theclear aqueous solution has pH value from about 6 to about 7.5, andwherein the clear aqueous solution is substantially free of solventother than water. In some embodiments, provided herein is a compositioncomprising Docetaxel and human serum albumin, wherein the Docetaxel andthe human serum albumin in the composition have a ratio by weight fromabout 1:80 to about 1:150, wherein the composition is a clear aqueoussolution when the composition is dissolved in an aqueous solution, andwherein the clear aqueous solution has pH value from about 6 to about7.5, and wherein the clear aqueous solution is free of solvent otherthan water.

In some embodiments, the composition forms a clear aqueous solution,when the composition is dissolved in an aqueous solution, wherein theclear aqueous solution has pH value from about 5 to about 8. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 5.5 to about 7.8. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6.5 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6 to about 6.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6.5 to about 7. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 7 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value about 6, about 6.1, about 6.2, about 6.3,about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, wherein after theclear aqueous solution is filtered by a 0.22 micron filter, the amountof Docetaxel in the filtered aqueous solution is at least 96% of thetotal amount of Docetaxel in the aqueous solution before the filtration.In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, wherein after theclear aqueous solution is filtered by a 0.22 micron filter, the amountof Docetaxel in the filtered aqueous solution is at least 97% of thetotal amount of Docetaxel in the aqueous solution before the filtration.In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, wherein after theclear aqueous solution is filtered by a 0.22 micron filter, the amountof Docetaxel in the filtered aqueous solution is at least 98% of thetotal amount of Docetaxel in the aqueous solution before the filtration.In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, wherein after theclear aqueous solution is filtered by a 0.22 micron filter, the amountof Docetaxel in the filtered aqueous solution is at least 99% of thetotal amount of Docetaxel in the aqueous solution before the filtration.In some embodiments, the aqueous formulation is substantially free ofsolvent other than water.

In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution, wherein after theclear aqueous solution is filtered by a 0.22 micron filter, the amountof Docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%,99%, or 99.5% of the total amount of Docetaxel in the aqueous solutionbefore the filtration, wherein the clear aqueous solution has pH valuefrom about 5 to about 8, and wherein the clear aqueous solution issubstantially free of solvent other than water. In some embodiments, thecomposition is a clear aqueous solution when the composition isdissolved in an aqueous solution, wherein after the clear aqueoussolution is filtered by a 0.22 micron filter, the amount of Docetaxel inthe filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5%of the total amount of Docetaxel in the aqueous solution before thefiltration, wherein the clear aqueous solution has pH value from about 6to about 7.5, and wherein the clear aqueous solution is substantiallyfree of solvent other than water. In some embodiments, the compositionis a clear aqueous solution when the composition is dissolved in anaqueous solution, wherein after the clear aqueous solution is filteredby a 0.22 micron filter, the amount of Docetaxel in the filtered aqueoussolution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount ofDocetaxel in the aqueous solution before the filtration, wherein theclear aqueous solution has pH value from about 5 to about 8, and whereinthe clear aqueous solution is free of solvent other than water. In someembodiments, the composition is a clear aqueous solution when thecomposition is dissolved in an aqueous solution, wherein after the clearaqueous solution is filtered by a 0.22 micron filter, the amount ofDocetaxel in the filtered aqueous solution is at least 96%, 97%, 98%,99%, or 99.5% of the total amount of Docetaxel in the aqueous solutionbefore the filtration, wherein the clear aqueous solution has pH valuefrom about 6 to about 7.5, and wherein the clear aqueous solution isfree of solvent other than water.

In some embodiments, the composition is an aqueous solution, whereinafter the aqueous solution is filtered by a 0.22 micron filter, theamount of Docetaxel in the filtered aqueous solution is at least 80% ofthe total amount of Docetaxel in the aqueous solution before thefiltration. In some embodiments, the composition is an aqueous solution,wherein after the aqueous solution is filtered by a 0.22 micron filter,the amount of Docetaxel in the filtered aqueous solution is at least 85%of the total amount of Docetaxel in the aqueous solution before thefiltration. In some embodiments, the composition is an aqueous solution,wherein after the aqueous solution is filtered by a 0.22 micron filter,the amount of Docetaxel in the filtered aqueous solution is at least 90%of the total amount of Docetaxel in the aqueous solution before thefiltration. In some embodiments, the aqueous formulation issubstantially free of solvent other than water. In some embodiments, theaqueous formulation is free of solvent other than water.

In some embodiments, the composition is a clear aqueous solution for atleast 3 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 6 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 24 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 3 days when the composition is dissolved in an aqueous solution.In some embodiments, the aqueous solution is substantially free ofsolvent other than water. In some embodiments, the aqueous solution freeof solvent other than water.

In some embodiments, the composition is a solid formulation. Forexample, the solid formulation can be produced in a uniform manner bylyophilization. A skilled artisan would recognize other methods, such asrotary evaporation, that can also produce solid formulations. In someembodiments, the pH of the solid formulation is neutral (e.g., pH of thecomposition is from about 5 to about 8, from about 5.5 to about 7.5, orfrom about 6 to about 7, or the pH of the composition is about 5, about5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5 or about 8).

In some embodiments, the composition is an aqueous formulation. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water. In some embodiments, the aqueousformulation includes water and water-miscible organic solvents includingat least one of polyethylene glycol 300, polyethylene glycol 400,ethanol, methanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide. For example, thewater-miscible organic solvent can include ethanol. In some embodiments,the aqueous formulation includes water and ethanol. In some embodiments,the water-miscible organic solvent can be a mixture of water-miscibleorganic solvents. In some embodiments, the pH of the aqueous formulation(e.g., clear aqueous solution) is neutral (e.g., pH of the compositionis from about 5 to about 8, from about 5.5 to about 7.5, or from about 6to about 7, or the pH od the composition is about 5, about 5.5, about 6,about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3,about 7.4, about 7.5 or about 8).

In some embodiments, the aqueous formulation can be free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation can be substantially free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In someembodiments, the aqueous formulation can be substantially free of asurfactant selected from the group consisting of CREMOPHOR® surfactantsand Polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueoussolution. For example, the formulation can be a clear and stable aqueoussolution reconstituted from a sterile lyophilized powder. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation is substantially free of solvent otherthan water. In some embodiments, the aqueous formulation is a clearaqueous solution, wherein the aqueous formulation is free of solventother than water.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline. In some embodiments, theaqueous formulation is a clear aqueous solution reconstituted from thesolid formulation (e.g. the sterile lyophilized powder) in 5% Dextrosesolution.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the aqueous formulation has pH value fromabout 5 to about 8. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline, wherein the aqueousformulation has pH value from about 5 to about 8. In some embodiments,the aqueous formulation is a clear aqueous solution reconstituted fromthe solid formulation (e.g. the sterile lyophilized powder) in 5%Dextrose solution, wherein the aqueous formulation has pH value fromabout 5 to about 8.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 5 to about 8. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 5 to about 8. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinthe pH of 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 5 to about 8. In some aspects of theaforementioned embodiments, the concentration of the reconstituted solidin the aqueous formulation is about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 150 mg or 200 mg per 1 ml of the aqueous solvent. Insome aspects of the aforementioned embodiments, the concentration of thereconstituted solid in the aqueous formulation is from about 10 mg per 1ml to about 500 mg per 1 ml of the aqueous solvent. In some aspects ofthe aforementioned embodiments, the concentration of the reconstitutedsolid in the aqueous formulation is from about 25 mg per 1 ml to about250 mg per 1 ml of the aqueous solvent. In some aspects of theaforementioned embodiments, the concentration of the reconstituted solidin the aqueous formulation is from about 30 mg per 1 ml to about 200 mgper 1 ml of the aqueous solvent. In some aspects of the aforementionedembodiments, the concentration of the reconstituted solid in the aqueousformulation is from about 40 mg per 1 ml to about 150 mg per 1 ml of theaqueous solvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 50 mg per 1 ml to about 125 mg per 1 ml of the aqueoussolvent.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 5 to about 8. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 6.7 to about 7.1. In some embodiments, the aqueous formulation isa clear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinthe pH of 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 6.7 to about 7.1. In some aspects ofthe aforementioned embodiments, the concentration of the reconstitutedsolid in the aqueous formulation is about 25 mg, about 50 mg, about 75mg, about 100 mg, about 150 mg or 200 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 10 mg per 1 ml to about 500 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 25 mg per 1 ml to about 250 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 30 mg per 1 ml to about 200 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 40 mg per 1 ml to about 150 mg per 1 ml of the aqueoussolvent. In some aspects of the aforementioned embodiments, theconcentration of the reconstituted solid in the aqueous formulation isfrom about 50 mg per 1 ml to about 125 mg per 1 ml of the aqueoussolvent.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the aqueous formulation has pH value fromabout 6 to about 7.5. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 0.9% saline, wherein the aqueousformulation has pH value from about 6 to about 7.5. In some embodiments,the aqueous formulation is a clear aqueous solution reconstituted fromthe solid formulation (e.g. the sterile lyophilized powder) in 5%Dextrose solution, wherein the aqueous formulation has pH value fromabout 6 to about 7.5.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value from about 6 to about 7.5. In someembodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in 0.9% saline solution, wherein the pH of 0.9% saline solutionis about 5.4, and wherein the aqueous formulation has pH value fromabout 6 to about 7.5. In some embodiments, the aqueous formulation is aclear aqueous solution reconstituted from the solid formulation (e.g.the sterile lyophilized powder) in 5% dextrose water solution, whereinpH of the 5% dextrose solution is about 4.4, and wherein the aqueousformulation has pH value from about 6 to about 7.5.

In some embodiments, the aqueous formulation is a clear aqueous solutionreconstituted from the solid formulation (e.g. the sterile lyophilizedpowder) in water, wherein the pH of water is about 7, and wherein theaqueous formulation has pH value of about 6, about 6.1, about 6.2, about6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9,about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, orabout 8. In some embodiments, the aqueous formulation is a clear aqueoussolution reconstituted from the solid formulation (e.g. the sterilelyophilized powder) in 0.9% saline solution, wherein the pH of 0.9%saline solution is about 5.4, and wherein the aqueous formulation has pHvalue of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5,about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments,the aqueous formulation is a clear aqueous solution reconstituted fromthe solid formulation (e.g. the sterile lyophilized powder) in 5%dextrose water solution, wherein pH of the 5% dextrose solution is about4.4, and wherein the aqueous formulation has pH value of about 6, about6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7,about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about7.4, about 7.5, or about 8.

In some embodiments, the aqueous formulation has pH value from about 5to about 8. In some embodiments, the aqueous formulation has pH valuefrom about 5.5 to about 7.8. In some embodiments, the aqueousformulation has pH value from about 6 to about 7.5. In some embodiments,the aqueous formulation has pH value from about 6.5 to about 7.5. Insome embodiments, the aqueous formulation has pH value from about 6 toabout 6.5. In some embodiments, the aqueous formulation has pH valuefrom about 6.5 to about 7. In some embodiments, the aqueous formulationhas pH value from about 7 to about 7.5. In some embodiments, the aqueousformulation has pH value about 6, about 6.1, about 6.2, about 6.3, about6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0,about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 5 toabout 8, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 5 to about 8, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 5.5 to about 7.8, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 5.5 to about7.8, and wherein the aqueous formulation is free of solvent other thanwater. In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 6 toabout 7.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 6 to about 7.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 6.5 to about 7.5, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 6.5 to about7.5, and wherein the aqueous formulation is free of solvent other thanwater. In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 6 toabout 6.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 6 to about 6.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value from about 6.5 to about 7, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value from about 6.5 to about 7,and wherein the aqueous formulation is free of solvent other than water.In some embodiments, the aqueous formulation is a clear aqueoussolution, wherein the aqueous formulation has pH value from about 7 toabout 7.5, and wherein the aqueous formulation is substantially free ofsolvent other than water. In some embodiments, the aqueous formulationis a clear aqueous solution, wherein the aqueous formulation has pHvalue from about 7 to about 7.5, and wherein the aqueous formulation isfree of solvent other than water. In some embodiments, the aqueousformulation is a clear aqueous solution, wherein the aqueous formulationhas pH value about 6, about 6.1, about 6.2, about 6.3, about 6.4, about6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1,about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueousformulation is substantially free of solvent other than water. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation has pH value about 6, about 6.1, about6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8,about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, orabout 7.5, and wherein the aqueous formulation is free of solvent otherthan water.

In some embodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 96% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 97% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 98% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 99% of the total amount ofDocetaxel in the aqueous solution before filtration. In someembodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 99.5% of the total amountof Docetaxel in the aqueous solution before filtration. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or99.5% of the total amount of Docetaxel in the aqueous solution beforefiltration, wherein the clear aqueous solution has pH value from about 5to about 8, and wherein the clear aqueous solution is substantially freeof solvent other than water. In some embodiments, after the aqueousformulation (e.g. a clear aqueous solution) is filtered by a 0.22 micronfilter, the amount of Docetaxel in the filtered aqueous solution is atleast 96%, 97%, 98%, 99%, or 99.5% of the total amount of Docetaxel inthe aqueous solution before filtration, wherein the clear aqueoussolution has pH value from about 6 to about 7.5, and wherein the clearaqueous solution is substantially free of solvent other than water. Insome embodiments, after the aqueous formulation (e.g. a clear aqueoussolution) is filtered by a 0.22 micron filter, the amount of Docetaxelin the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or99.5% of the total amount of Docetaxel in the aqueous solution beforefiltration, wherein the clear aqueous solution has pH value from about 5to about 8, and wherein the clear aqueous solution is free of solventother than water. In some embodiments, after the aqueous formulation(e.g. a clear aqueous solution) is filtered by a 0.22 micron filter, theamount of Docetaxel in the filtered aqueous solution is at least 96%,97%, 98%, 99%, or 99.5% of the total amount of Docetaxel in the aqueoussolution before filtration, wherein the clear aqueous solution has pHvalue from about 6 to about 7.5, and wherein the clear aqueous solutionis free of solvent other than water.

In some embodiments, the aqueous formulation is a clear aqueous solutionfor at least 3 hours. In some embodiments, the aqueous formulation is aclear aqueous solution for at least 3 hours at a temperature from about1° C. to about 35° C., about 1° C. to about 10° C., about 10° C. toabout 20° C., about 20° C. to about 35° C., or about 1° C., about 5° C.,about 10° C., about 15° C., about 20° C., about 25° C., about 30° C., orabout 35° C. In some embodiments, the aqueous formulation is a clearaqueous solution for at least 6 hours. In some embodiments, the aqueousformulation is a clear aqueous solution for at least 6 hours at atemperature from about 1° C. to about 35° C., about 1° C. to about 10°C., about 10° C. to about 20° C., about 20° C. to about 35° C., or about1° C., about 5° C., about 10° C., about 15° C., about 20° C., about 25°C., about 30° C., or about 35° C. In some embodiments, the aqueousformulation is a clear aqueous solution for at least 24 hours. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 24 hours at a temperature from about 1° C. to about 35° C., about1° C. to about 10° C., about 10° C. to about 20° C., about 20° C. toabout 35° C., or about 1° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., or about 35° C. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 3 days. In some embodiments, the aqueous formulation is a clearaqueous solution for at least 3 days when dissolved in an aqueoussolution at a temperature from about 1° C. to about 35° C., about 1° C.to about 10° C., about 10° C. to about 20° C., about 20° C. to about 35°C., or about 1° C., about 5° C., about 10° C., about 15° C., about 20°C., about 25° C., about 30° C., or about 35° C. In some embodiments, theaqueous formulation is substantially free of solvent other than water.In some embodiments, the aqueous formulation is free of solvent otherthan water.

Also, provided herein is a pharmaceutical composition comprising thecomposition comprising the Docetaxel and the human serum albumin asdescribed herein, and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is free of asurfactant, such as CREMOPHOR® surfactants and Polysorbate 80.

In some embodiments, the pharmaceutical composition is substantiallyfree of a surfactant, such as CREMOPHOR® surfactants and Polysorbate 80.

Also, provided herein is a method of treating a proliferative diseasecomprising the step of administering to a subject in need thereof apharmaceutical composition comprising the composition comprising theDocetaxel and the human serum albumin as described herein, and apharmaceutically acceptable carrier.

Also, provided herein is a method of treating a cancer (e.g., any one ofcancers described herein), the method comprising the step ofadministering to a subject in need thereof of a therapeuticallyeffective amount of a pharmaceutical composition comprising thecomposition comprising the Docetaxel and the human serum albumin asdescribed herein, and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is any one of cancers described herein.

In some embodiments, the cancer is a solid tumor cancer. In someembodiments, the cancer is selected from the group consisting of breastcancer, non-small cell lung cancer, prostate cancer, gastric cancer,head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi'ssarcoma. In some embodiments, the cancer is a breast cancer. In someembodiments, the cancer is a non-small cell lung cancer. In someembodiments, the cancer is a prostate cancer. In some embodiments, thecancer is a gastric cancer. In some embodiments, the cancer is a headand neck cancer. In some embodiments the cancer is an ovarian cancer. Insome embodiments, the cancer is a pancreatic cancer. In someembodiments, the cancer is a Kaposi's sarcoma.

In some embodiments, the method of treating cancer (e.g., any one ofcancers described herein) comprises the step of administering to asubject in need thereof a therapeutically effective amount of apharmaceutical composition comprising the composition comprising theDocetaxel and the human serum albumin as described herein, and atherapeutically effective amount of at least one inhibitor of thekinases for the treatment of cancer described herein.

In some embodiments, the method of treating cancer (e.g. any one ofcancers described herein) comprises the step of administering to asubject in need thereof a therapeutically effective amount of apharmaceutical composition comprising the composition comprising theDocetaxel and the human serum albumin as described herein, and atherapeutically effective amount of at least one anti-cancer drugdescribed herein.

In some embodiments, a composition comprising the Docetaxel and thehuman serum albumin as described herein and an anti-cancer drug areadministered simultaneously.

In some embodiments, a composition comprising the Docetaxel and thehuman serum albumin as described herein and an anti-cancer drug areadministered consecutively.

The composition comprising the Docetaxel and the human serum albumindescribed herein can be administered to an individual, such as human,via various routes, such as parenterally, including intravenous,intra-arterial, intraperitoneal, intrapulmonary, oral, inhalation,intravesicular, intramuscular, intra-tracheal, subcutaneous,intraocular, intrathecal, or transdermal. For example, the compositioncan be administered by inhalation to treat conditions of the respiratorytract. The composition can be used to treat respiratory conditions suchas pulmonary fibrosis, broncheolitis obliterans, lung cancer,bronchoalveolar carcinoma, and the like. In some embodiments, thecomposition is administrated intravenously.

The methods described herein may be performed alone or in conjunctionwith another therapy, such as surgery, radiation, chemotherapy,immunotherapy, gene therapy, and the like. Additionally, a person havinga greater risk of developing the proliferative disease may receivetreatments to inhibit or and/or delay the development of the disease.

As will be understood by those of ordinary skill in the art, theappropriate doses of Docetaxel will be approximately those alreadyemployed in clinical therapies wherein Docetaxel is administered aloneor in combination with other chemotherapeutic agents. Variation indosage will likely occur depending on the condition being treated.Appropriate effective doses will also vary, as recognized by thoseskilled in the art, depending on the severity of the disease, the routeof administration, the sex, age and general health condition of thesubject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents, and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forDocetaxel.

Also, provided herein is a composition consisting essentially ofDocetaxel and human serum albumin, wherein the Docetaxel and the humanserum albumin in the composition have a ratio by weight from about 1:50to about 1:1000. In some embodiments, the pH of the composition isneutral (e.g., pH of the composition is from about 5 to about 8, fromabout 5.5 to about 7.5, or from about 6 to about 7, or the pH of thecomposition is about 5, about 5.5, about 6, about 6.1, about 6.2, about6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9,about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, orabout 8).

In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:50 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:60 to about 1:300. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:250. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:200. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:150. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:120. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:1000.In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight of about 1:60, about 1:70, about1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130,about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240,or about 1:250.

In some embodiments, the human serum albumin is a native human serumalbumin. In some embodiments, the human serum albumin is a recombinanthuman serum albumin. In some embodiments, the human serum albumin is afatty acid free human serum albumin. In some embodiments, the humanserum albumin is essentially fatty acid free. In some embodiments, thehuman serum albumin contains no more than two moles of fatty acids boundto one mole of human serum albumin. In some embodiments, the human serumalbumin contains no more than one mole of fatty acids bound to one moleof human serum albumin. In some embodiments, human serum albumincontains no more than 0.5 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.1 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.05 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.01 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.001 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0005 moles of fatty acids bound to one mole ofhuman serum albumin. In some embodiments, the human serum albumincontains no more than 0.0001 moles of fatty acids bound to one mole ofhuman serum albumin.

In some embodiments, the Docetaxel can be a pharmaceutically acceptablesalt of Docetaxel. In some embodiments, the Docetaxel can be a Docetaxelwith three equivalents of the water solvate. In some embodiments,Docetaxel can be any one of crystal forms, amorphous forms, solvates andhydrates as described herein.

In some embodiments, the composition is a clear aqueous solution whenthe composition is dissolved in an aqueous solution. In someembodiments, the aqueous solution is substantially free of solvent otherthan water. In some embodiments, the aqueous solution is free of solventother than water.

In some embodiments, the composition forms a clear aqueous solution,when the composition is dissolved in an aqueous solution, wherein theclear aqueous solution has pH value from about 5 to about 8. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 5.5 to about 7.8. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6.5 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6 to about 6.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 6.5 to about 7. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value from about 7 to about 7.5. In someembodiments, the composition forms a clear aqueous solution, when thecomposition is dissolved in an aqueous solution, wherein the clearaqueous solution has pH value about 6, about 6.1, about 6.2, about 6.3,about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the composition is a clear aqueous solution for atleast 3 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 6 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 24 hours when the composition is dissolved in an aqueous solution.In some embodiments, the composition is a clear aqueous solution for atleast 3 days when the composition is dissolved in an aqueous solution.In some embodiments, the aqueous solution is substantially free ofsolvent other than water. In some embodiments, the aqueous solution freeof solvent other than water.

In some embodiments, the composition is a solid formulation. Forexample, the solid formulation can be produced in a uniform manner bylyophilization. A skilled artisan would recognize other methods, such asrotary evaporation, that can also produce solid formulations.

In some embodiments, the composition is an aqueous formulation. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the aqueous formulation is a clear aqueoussolution. For example, the formulation can be a clear and stable aqueoussolution reconstituted from a sterile lyophilized powder. In someembodiments, the aqueous formulation is a clear aqueous solution,wherein the aqueous formulation is substantially free of solvent otherthan water. In some embodiments, the aqueous formulation is a clearaqueous solution, wherein the aqueous formulation is free of solventother than water.

In some embodiments, the aqueous formulation has pH value from about 5to about 8. In some embodiments, the aqueous formulation has pH valuefrom about 5.5 to about 7.8. In some embodiments, the aqueousformulation has pH value from about 6 to about 7.5. In some embodiments,the aqueous formulation has pH value from about 6.5 to about 7.5. Insome embodiments, the aqueous formulation has pH value from about 6 toabout 6.5. In some embodiments, the aqueous formulation has pH valuefrom about 6.5 to about 7. In some embodiments, the aqueous formulationhas pH value from about 7 to about 7.5. In some embodiments, the aqueousformulation has pH value about 6, about 6.1, about 6.2, about 6.3, about6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0,about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof solvent other than water.

In some embodiments, the aqueous formulation is a clear aqueous solutionfor at least 3 hours. In some embodiments, the aqueous formulation is aclear aqueous solution for at least 6 hours. In some embodiments, theaqueous formulation is a clear aqueous solution for at least 6 hours ata temperature from about 1° C. to about 35° C., about 1° C. to about 10°C., about 10° C. to about 20° C., about 20° C. to about 35° C., or about1° C., about 5° C., about 10° C., about 15° C., about 20° C., about 25°C., about 30° C., or about 35° C. In some embodiments, the aqueousformulation is a clear aqueous solution for at least 24 hours. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 24 hours at a temperature from about 1° C. to about 35° C., about1° C. to about 10° C., about 10° C. to about 20° C., about 20° C. toabout 35° C., or about 1° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., or about 35° C. In someembodiments, the aqueous formulation is a clear aqueous solution for atleast 3 days. In some embodiments, the aqueous formulation is a clearaqueous solution for at least 3 days when dissolved in an aqueoussolution at a temperature from about 1° C. to about 35° C., about 1° C.to about 10° C., about 10° C. to about 20° C., about 20° C. to about 35°C., or about 1° C., about 5° C., about 10° C., about 15° C., about 20°C., about 25° C., about 30° C., or about 35° C. In some embodiments, theaqueous formulation is substantially free of solvent other than water.In some embodiments, the aqueous formulation is free of solvent otherthan water.

Also, provided herein is a pharmaceutical composition comprising thecomposition consisting essentially of the Docetaxel and the human serumalbumin as described herein, and a pharmaceutically acceptable carrier.

Also, provided herein is a method of treating a cancer (e.g., any one ofcancers described herein), the method comprising the step ofadministering to a subject in need thereof of a therapeuticallyeffective amount of a pharmaceutical composition comprising thecomposition consisting essentially of the Docetaxel and the human serumalbumin as described herein, and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is any one of cancers described herein.

In some embodiments, the cancer is a solid tumor cancer. In someembodiments, the cancer is selected from the group consisting of breastcancer, non-small cell lung cancer, prostate cancer, gastric cancer,head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi'ssarcoma. In some embodiments, the cancer is a breast cancer. In someembodiments, the cancer is a non-small cell lung cancer. In someembodiments, the cancer is a prostate cancer. In some embodiments, thecancer is a gastric cancer. In some embodiments, the cancer is a headand neck cancer. In some embodiments the cancer is an ovarian cancer. Insome embodiments, the cancer is a pancreatic cancer. In someembodiments, the cancer is a Kaposi's sarcoma.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of any one of diseases ordisorders referred to herein, which include one or more containerscontaining a pharmaceutical composition comprising a composition ofdocetaxel and the human serum albumin as described herein. Such kits canfurther include, if desired, one or more of various conventionalpharmaceutical kit components, such as, for example, containers with oneor more pharmaceutically acceptable carriers (e.g., water, 0.9% saline,or 5% dextrose), additional containers, etc., as will be readilyapparent to those skilled in the art. Instructions, either as inserts oras labels, indicating quantities of the components to be administered(e.g., dosage amounts as described herein), guidelines foradministration, and/or guidelines for mixing the components, can also beincluded in the kit.

Methods of Making

Also, provided herein are several methods to prepare a compositioncomprising a non-covalently bound complex comprising the Docetaxel andthe human serum albumin as described herein, a composition comprisingthe Docetaxel and the human serum albumin as described herein, or acomposition consisting essentially of the Docetaxel and the human serumalbumin as described herein.

In some embodiments, the present disclosure provides a method ofpreparing a composition comprising a non-covalently bound complexcomprising Docetaxel and human serum albumin, wherein the molar ratio ofDocetaxel and human serum albumin in the complex is from about 0.1:1 toabout 5:1.

In some embodiments, the present disclosure provides a method ofpreparing a composition comprising Docetaxel and human serum albumin,wherein the molar ratio of Docetaxel and the human serum albumin in thecomposition is from about 0.1:1 to about 5:1.

In some embodiments, the present disclosure provides a method ofpreparing a composition comprising Docetaxel and human serum albumin,wherein the molar ratio of Docetaxel and the human serum albumin in thecomposition is from about 0.1:1 to about 5:1, wherein the compositionforms a clear aqueous solution when the composition is dissolved in anaqueous solution, and wherein the solubility of the composition in theaqueous solution is at least 10 mg/ml.

In some embodiments, the present disclosure provides a method ofpreparing a composition comprising Docetaxel and human serum albumin,wherein the Docetaxel and the human serum albumin in the compositionhave a ratio by weight from about 1:50 to about 1:1000.

In some embodiments, the present disclosure provides a method ofpreparing a composition consisting essentially of Docetaxel and humanserum albumin, wherein the Docetaxel and the human serum albumin in thecomposition have a ratio by weight from about 1:50 to about 1:1000.

In some embodiments, the method comprises mixing an organic solution ofDocetaxel in a polar water-miscible organic solvent and a first aqueoussolution containing human serum albumin to form a second aqueoussolution, wherein the second aqueous solution is a clear aqueoussolution.

In some embodiments, the method further comprises removing said polarwater-miscible organic solvent and water from the second aqueoussolution.

A non-limiting preferred method is as follows.

Formation of the Organic Solution

In some embodiments, Docetaxel is dissolved in a polar organic solvent(e.g., an alcohol such as methanol, ethanol, isopropanol, and/orn-butanol; THF, CH₃CN; DMF; or mixtures thereof) to form an organicsolution.

As used herein, the term “organic solution” refers to a solution whereinat least one solvent is a non-aqueous solvent and the weight % of thenon-aqueous solvent in the mixture of solvents is at least 50%, at least60%, at least 70% or at least 90%. In some embodiments, organic solutionis a solution in which does not comprise water as a solvent.

In some embodiments, the terms “organic solvent” and “non-aqueoussolvent” are used interchangeably and refer to a liquid comprising is atleast 50%, at least 60%, at least 70%, at least 90%, or at least 95% ofa solvent other than water.

The polar organic solvent is miscible in water. In some embodiments, thepolar organic solvent is an alcohol. In some embodiments, the polarorganic solvent is ethanol or methanol, or mixtures thereof. In someembodiments, the polar organic solvent can be ethanol. In someembodiments, the polar organic solvent is methanol.

In some embodiments, the amount of polar organic solvent is from about0.005 mL to about 10 mL per 1 mg of Docetaxel. In some embodiments, theamount of polar organic solvent is from about 0.01 mL to about 5 mL per1 mg of Docetaxel. In some embodiments, the amount of polar organicsolvent is from about 0.05 mL to about 5 mL per 1 mg of Docetaxel. Insome embodiments, the amount of polar organic solvent is from about 0.1mL to about 2.0 mL per 1 mg of Docetaxel. In some embodiments, theamount of polar organic solvent is from about 0.4 mL to about 2.0 mL per1 mg of Docetaxel. In some embodiments, the amount of polar organicsolvent is from about 0.5 mL to about 1.7 mL per 1 mg of Docetaxel. Insome embodiments, the amount of polar organic solvent is about 0.4 mL,about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 1 mL,about 1.2 mL, about 1.25 mL, about 1.35 mL, about 1.4 mL, about 1.45 mL,about 1.5 mL, about 1.6 mL, about 1.7 mL, or about 2.0 mL per 1 mg ofDocetaxel.

Formation of the First Aqueous Solution

In some embodiments, a defined amount of human serum albumin isdissolved in an amount of water to form a first aqueous solution.

In some embodiments, the amount of aqueous solvent (e.g., water, saline,dextrose solution, or a buffer (e.g., any one of buffers describedherein)) to prepare the first aqueous solution is from about 1 mL toabout 1000 L, from about 2 mL to about 100 L, from about 3 mL to about10 L, from about 4 mL to about 1 L, from about 5 mL to about 200 mL,from about 6 mL to about 100 mL, from about 10 mL to about 90 mL, fromabout 4 mL to about 20 mL, or from about 10 mL to about 20 mL. In someembodiments, the amount of water to prepare the first aqueous solutionis about 4 mL, about 4.5 mL, about 5 mL, about 6 mL, about 10 mL, about16 mL, about 17 mL, about 90 mL, or about 100 mL.

In some embodiments, the amount of HSA prepare the first aqueoussolution is from about 100 mg to about 500 kg, from about 150 mg toabout 100 kg, from about 200 mg to about 10 kg, from about 300 mg toabout 500 g, from about 200 mg to about 100 g, or from about 200 mg toabout 10 g. In some embodiments, the amount of HSA prepare the firstaqueous solution is about 100 mg, about 200 mg, about 300 mg, about 600mg, about 700 mg, about 800 mg, about 850 mg, about 900 mg, about 4500mg, or about 5000 mg.

In some embodiments, the amount of aqueous solvent in the first aqueoussolution is from about 0.01 mL to about 10 mL per 1 mg of human serumalbumin. In some embodiments, the amount of aqueous solvent in the firstaqueous solution is from about 0.01 mL to about 5 mL per 1 mg of humanserum albumin. In some embodiments, the amount of aqueous solvent in thefirst aqueous solution is from about 0.01 mL to about 1 mL per 1 mg ofhuman serum albumin. In some embodiments, the amount of aqueous solventin the first aqueous solution is from about 0.01 mL to about 0.5 mL per1 mg of human serum albumin. In some embodiments, the amount of aqueoussolvent in the first aqueous solution is from about 0.01 mL to about 0.1mL per 1 mg of human serum albumin. In some embodiments, the amount ofaqueous solvent in the first aqueous solution is from about 0.01 mL toabout 0.05 mL per 1 mg of human serum albumin. In some embodiments, theamount of aqueous solvent in the first aqueous solution is from about0.015 mL to about 0.04 mL per 1 mg of human serum albumin. In someembodiments, the amount of aqueous solvent in the first aqueous solutionis about 0.01 mL, about 0.015 mL, about 0.02 mL, about 0.025 mL, about0.03 mL, about 0.035 mL, about 0.04 mL, about 0.045 mL, or about 0.05 mLper 1 mg of human serum albumin. In some embodiments, the amount ofaqueous solvent in the first aqueous solution about 0.02 mL per 1 mg ofhuman serum albumin.

In some embodiments, the resulting composition comprising the Docetaxeland the human serum albumin can have any molar ratio or any ratio byweight of the Docetaxel to the human serum albumin as described herein.In some embodiments, the human serum albumin is a fatty acid free humanserum albumin. In some embodiments, the human serum albumin isessentially fatty acid free.

In some embodiments, the preparation of the organic solution and thepreparation of the first aqueous solution are performed concurrently.

In some embodiments, the preparation of the organic solution and thepreparation of the first aqueous solution are performed sequentially. Insome embodiments, the preparation of the organic solution is performedbefore the preparation of the first aqueous solution. In someembodiments, the preparation of the first aqueous solution is performedbefore the preparation of the organic solution.

In some embodiments, the range of pH in the first aqueous solution isfrom about 3 to about 9, from about 4 to about 8, from about 5 to about8, from about 5 to about 7, from about 6 to about 7, from about 3 toabout 5, from about 3 to about 7, from about 4 to about 6, or from about6 to about 6.5. In some embodiments, the pH of the first aqueoussolution is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6,about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about8.

Formation of the Second Aqueous Solution

In some embodiments, the organic solution of Docetaxel is mixed with thefirst aqueous solution of human serum albumin to form a second aqueoussolution. In some embodiments, the second aqueous solution is a clearaqueous solution.

In some embodiments, the volume ratio of the amount of water to theamount of the polar organic solvent is in a range from about 1:1 toabout 1000:1. In some embodiments, the volume ratio of the amount ofwater to the amount of the polar organic solvent is in a range fromabout 1.5:1 to about 100:1. In some embodiments, the volume ratio of theamount of water to the amount of the polar organic solvent is in a rangefrom about 1.5:1 to about 20:1. In some embodiments, the volume ratio ofthe amount of water to the amount of the polar organic solvent is in arange from about 1.5:1 to about 10:1. In some embodiments, the volumeratio of the amount of water to the amount of the polar organic solventis in a range from about 2:1 to about 10:1. In some embodiments, thevolume ratio of the amount of water to the amount of the polar organicsolvent is about 1.5:1, about 2:1, about 2.2:1, about 2.3:1, about2.4:1, about 2.5:1, about 3:1, about 4:1, about 5:1, about 6:1, about7:1, about 8:1, about 9:1, or about 10:1.

In some embodiments, the organic solution is added to the first aqueoussolution to form a second aqueous solution. In some embodiments, theorganic solution is added dropwise to the first aqueous solution to forma second aqueous solution. In some embodiments, the first aqueoussolution is added to the organic solution to form a second aqueoussolution. In some embodiments, the mixing is performed with agitation.In some embodiments, the mixing is performed with stirring. In someembodiments, the mixing is performed with shaking.

In some embodiments, the addition is done at the temperature from about0° C. to about 35° C. In some embodiments, the addition is done at thetemperature from about 0° C. to about 25° C. In some embodiments, theaddition is done at the temperature from about 0° C. to about 10° C. Insome embodiments, the addition is done at the temperature from about 0°C. to about 5° C. In some embodiments, the addition is done at thetemperature about 0° C. In some embodiments, the addition is done at thetemperature about 5° C. In some embodiments, the addition is done at thetemperature about 10° C.

In some embodiments, the time of addition is in a range from about 0.1min to about 24 hours. In some embodiments, the time of addition is in arange from about 1 min to about 2 hour. In some embodiments, the time ofaddition is in a range from about 1 min to about 1 hour. In someembodiments, the time of addition is in a range from about 5 min toabout 30 min.

In some embodiments, the range of pH in the second aqueous solution isfrom about 3 to about 9, from about 4 to about 8, from about 5 to about8, from about 5 to about 7, from about 6 to about 7, from about 3 toabout 5, from about 3 to about 7, from about 4 to about 6, or from about6 to about 6.5. In some embodiments, the pH of the second aqueoussolution is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6,about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about8.

Removal of Organic Solvent

In some embodiments, upon completion of mixing of the organic solutionwith the first aqueous solution to form the second aqueous solution, thepolar organic solvent is removed from the second aqueous solution.

In some embodiments, the polar organic solvent is removed under reducedpressure. In some embodiments, the polar organic solvent is removedusing rotary evaporation. In some embodiments, the polar organic solventis removed under a vacuum.

In some embodiments, the removal of the polar organic solvent yields aclear aqueous solution. In some embodiments, water is removed from theaqueous under a vacuum. In some embodiments, water is removed from theaqueous solution using rotary evaporation. In some embodiments, water isremoved from the aqueous solution by lyophilization.

In some embodiments, the solvents including both water and organicsolvent are removed from the second aqueous solution simultaneously toprovide a solid composition. In some embodiments, the solvents areremoved under a vacuum. In some embodiments, the solvents are removedusing rotary evaporation. In some embodiments, the solvents are removedby lyophilization. In some embodiments, the second aqueous solution wasfiltered before removal of the solvents.

Removal of Water from the Second Aqueous Solution

In some embodiments, upon removal of the organic solvent from the secondaqueous solution, the water can be removed from the second aqueoussolution to provide a solid.

In some embodiments, the second aqueous solution is filtered beforeremoval of water. For example, the second aqueous solution can befiltered by a 0.22 micron filter before removal of water.

As used herein, the term “micron” refers to a unit of measure of oneone-thousandth of a millimeter.

In some embodiments, the water is removed under a vacuum. In someembodiments, the water is removed using rotary evaporation. In someembodiments, the water is removed by lyophilization.

In some embodiments, the amount of docetaxel that is bound to the HSA(e.g., non-covalently) in the solid composition comprising thecomposition comprising docetaxel and HSA (as described herein) is atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, at least 99%, or about 100% of the total aboutof docetaxel in the solid composition.

Reconstitution of the Solid

In some embodiments the solid composition comprising the Docetaxel andthe human serum albumin (e.g., the solid composition prepared byremoving organic solvent from the second aqueous solution and removingwater from the second aqueous solution) is mixed with a water solution.In some embodiments, the water solution is a saline solution. In someembodiments, the water solution is a 5% Dextrose water solution. In someembodiments, the mixing is the addition of the water solution to thesolid. In some embodiments, the mixing is the addition of the solid tothe water solution. In some embodiments, the mixing reconstitutes thesolid. In some embodiments, the mixing yields a clear aqueous solution.In some embodiments, the range of pH in the reconstituted solution isfrom about 5 to about 8, from about 5 to about 7, from about 6 to about7, from about 6.5 to about 7.5, from about 4 to about 6, or from about 6to about 6.5. In some embodiments, the pH of the reconstituted solutionis about 5, about 6, about 6.4, about 6.5, about 6.6, about 6.7, about6.8, about 6.9, about 7, about 7.1, about 7.5, or about 8.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Methods and materials aredescribed herein for use in the present disclosure; other suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, and otherreferences mentioned herein are incorporated by reference in theirentirety. In case of conflict, the present specification, includingdefinitions, will control.

Composition Prepared by the Process

In some embodiments, the present disclosure provides a compositioncomprising docetaxel and human serum albumin, wherein the weight ratioof docetaxel and the human serum albumin in the composition is fromabout 1:50 to about 1:1000, produced by a method comprising the stepsof:

(i) obtaining an organic solution of docetaxel in a polar water-miscibleorganic solvent;

(ii) obtaining a first aqueous solution of human serum albumin; and

(iii) mixing the organic solution of docetaxel and the first aqueoussolution of human serum albumin to obtain a second aqueous solutioncomprising the composition comprising docetaxel and human serum albumin.

In some embodiments, the range of pH in the first aqueous solution isfrom about 3 to about 9, from about 4 to about 8, from about 5 to about8, from about 5 to about 7, from about 6 to about 7, from about 3 toabout 5, from about 3 to about 7, from about 4 to about 6, or from about6 to about 6.5. In some embodiments, the pH of the first aqueoussolution is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6,about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about8.

In some embodiments, the range of pH in the second aqueous solution isfrom about 3 to about 9, from about 4 to about 8, from about 5 to about8, from about 5 to about 7, from about 6 to about 7, from about 3 toabout 5, from about 3 to about 7, from about 4 to about 6, or from about6 to about 6.5. In some embodiments, the pH of the second aqueoussolution is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6,about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about8.

In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:50 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:60 to about 1:300. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:250. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:200. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:120. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:1000. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:1000.In some embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:70 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:80 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:90 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight from about 1:100 to about 1:500. Insome embodiments, the Docetaxel and the human serum albumin in thecomposition are in a ratio by weight of about 1:60, about 1:70, about1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130,about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240,or about 1:250.

In some embodiments, the docetaxel can be a pharmaceutically acceptablesalt of Docetaxel. In some embodiments, the docetaxel can be a docetaxelwith three equivalents of the water solvate. In some embodiments,docetaxel can be any one of crystal forms, amorphous forms, solvates andhydrates as described herein.

In some embodiments, the human serum albumin is essentially fatty acidfree.

In some embodiments, the composition comprises a non-covalently boundcomplex comprising docetaxel and human serum albumin.

In some embodiments, the amount of the polar water-miscible organicsolvent in the organic solution is from about 0.01 mL to about 5 mL per1 mg of docetaxel.

In some embodiments, the amount of the polar water-miscible organicsolvent in the organic solution is from about from about 0.1 mL to about2.0 mL per 1 mg of docetaxel.

In some embodiments, the amount of the polar water-miscible organicsolvent in the organic solution is from about 0.4 mL to about 2.0 mL per1 mg of docetaxel.

In some embodiments, the amount of the polar water-miscible organicsolvent in the organic solution is from about 0.5 mL to about 1.7 mL per1 mg of docetaxel.

In some embodiments, the amount of organic solvent is from about 0.005mL to about 10 mL per 1 mg of Docetaxel. In some embodiments, the amountof organic solvent is from about 0.01 mL to about 5 mL per 1 mg ofDocetaxel. In some embodiments, the amount of organic solvent is fromabout 0.05 mL to about 5 mL per 1 mg of Docetaxel. In some embodiments,the amount of organic solvent is from about 0.1 mL to about 2.0 mL per 1mg of Docetaxel. In some embodiments, the amount of organic solvent isfrom about 0.4 mL to about 2.0 mL per 1 mg of Docetaxel. In someembodiments, the amount of organic solvent is from about 0.5 mL to about1.7 mL per 1 mg of Docetaxel. In some embodiments, the amount of organicsolvent is about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about0.8 mL, about 1 mL, about 1.2 mL, about 1.25 mL, about 1.35 mL, about1.4 mL, about 1.45 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, orabout 2.0 mL per 1 mg of Docetaxel.

In some embodiments, the amount of aqueous solvent in the first aqueoussolution is from about 0.005 mL to about 0.05 mL per 1 mg of human serumalbumin.

In some embodiments, the amount of aqueous solvent in the first aqueoussolution is from about 0.01 mL to about 0.05 mL per 1 mg of human serumalbumin.

In some embodiments, the amount of aqueous solvent in the first aqueoussolution is from about 0.015 mL to about 0.04 mL per 1 mg of human serumalbumin.

In some embodiments, the amount of aqueous solvent in the first aqueoussolution is from about 0.01 mL to about 10 mL per 1 mg of human serumalbumin. In some embodiments, the amount of aqueous solvent in the firstaqueous solution is from about 0.01 mL to about 5 mL per 1 mg of humanserum albumin. In some embodiments, the amount of aqueous solvent in thefirst aqueous solution is from about 0.01 mL to about 1 mL per 1 mg ofhuman serum albumin. In some embodiments, the amount of aqueous solventin the first aqueous solution is from about 0.01 mL to about 0.5 mL per1 mg of human serum albumin. In some embodiments, the amount of aqueoussolvent in the first aqueous solution is from about 0.01 mL to about 0.1mL per 1 mg of human serum albumin. In some embodiments, the amount ofaqueous solvent in the first aqueous solution is from about 0.01 mL toabout 0.05 mL per 1 mg of human serum albumin. In some embodiments, theamount of aqueous solvent in the first aqueous solution is from about0.015 mL to about 0.04 mL per 1 mg of human serum albumin. In someembodiments, the amount of aqueous solvent in the first aqueous solutionis about 0.01 mL, about 0.015 mL, about 0.02 mL, about 0.025 mL, about0.03 mL, about 0.035 mL, about 0.04 mL, about 0.045 mL, or about 0.05 mLper 1 mg of human serum albumin. In some embodiments, the amount ofaqueous solvent in the first aqueous solution about 0.02 mL per 1 mg ofhuman serum albumin.

In some embodiments, the polar water-miscible organic solvent is analcohol selected from the group consisting of methanol, ethanol,isopropanol, n-butanol, and mixtures thereof.

In some embodiments, the polar water-miscible organic solvent isselected from methanol, ethanol, and mixtures thereof.

In some embodiments, the polar water-miscible organic solvent ismethanol.

In some embodiments, the aqueous solvent is water.

In some embodiments, the mixing comprises adding the organic solution tothe first aqueous solution. In some embodiments, wherein the mixingcomprises adding the first aqueous solution to the organic solution. Insome embodiments, the adding is carried out dropwise. In someembodiments, the adding is carried out for a period of time from severalminutes to several hours. In some embodiments, the adding is carried outfor a period of time from 2 min to 24 hours. In some embodiments, theadding is carried out for a period of time from 2 min minutes to 12hours, from 2 min to 6 hours, from 3 min to 3 hours, from 2 min to 1hour, from 2 min to 30 min, or from 2 min to 25 min.

In some embodiments, the mixing is carried out at a temperature fromabout 0° C. to about 25° C. In some embodiments, mixing is carried outat ambient temperature (e.g., about 25° C.). In some embodiments, themixing is carried out at a temperature from about 0° C. to about 5° C.In some embodiments, the mixing is carried out at about 0° C.

In some embodiments, the volume ratio of the amount of aqueous solventto the amount of the organic solvent in the second aqueous solution isin a range from about 1:1 to about 1000:1. In some embodiments, thevolume ratio of the amount of aqueous solvent to the amount of theorganic solvent in the second aqueous solution is in a range from about1.5:1 to about 100:1. In some embodiments, the volume ratio of theamount of aqueous solvent to the amount of the organic solvent in thesecond aqueous solution is in a range from about 1.5:1 to about 20:1. Insome embodiments, the volume ratio of the amount of aqueous solvent tothe amount of the organic solvent in the second aqueous solution is in arange from about 1.5:1 to about 10:1. In some embodiments, the volumeratio of the amount of aqueous solvent to the amount of the organicsolvent in the second aqueous solution is in a range from about 2:1 toabout 10:1. In some embodiments, the volume ratio of the amount ofaqueous solvent to the amount of the organic solvent in the secondaqueous solution is about 1.5:1, about 2:1, about 2.2:1, about 2.3:1,about 2.4:1, about 2.5:1, about 3:1, about 4:1, about 5:1, about 6:1,about 7:1, about 8:1, about 9:1, or about 10:1. In some embodiments, theaqueous solvent is water. In some embodiments, the aqueous solvent iswater and the organic solvent is an alcohol. In some embodiments, theaqueous solvent is water and the organic solvent is methanol.

In some embodiments, the composition is prepared by further comprisingthe step of removing the polar water-miscible organic solvent from thesecond aqueous solution to obtain a third aqueous solution comprisingthe composition comprising docetaxel and human serum albumin. In someembodiments, the composition is prepared by further comprising the stepof removing aqueous solvent from the third aqueous solution to obtainthe composition comprising docetaxel and human serum albumin.

In some embodiments, the composition is prepared by further comprisingthe step of removing the organic solvent (e.g. methanol) and the aqueoussolvent (e.g., water) from the second aqueous solution to obtain thecomposition comprising docetaxel and human serum albumin.

In some embodiments, the removing as carried out in vacuum (e.g., usingthe rotovap). In some embodiments, the removing is carried out bylyophilization.

In some embodiments, the composition forms a clear aqueous solution whenthe composition is dissolved in an aqueous solvent, and wherein thesolubility of the composition in the aqueous solution is at least 10mg/ml.

In some embodiments, the composition is a solid formulation

In some embodiments, the composition is an aqueous formulation. In someembodiments, the aqueous formulation is substantially free of solventother than water. In some embodiments, the aqueous formulation is freeof a surfactant. In some embodiments, the surfactant is selected fromthe group consisting of CREMOPHOR® surfactants and Polysorbate 80. Insome embodiments, the aqueous formulation is a clear aqueous solution.In some embodiments, the aqueous formulation is a clear aqueous solutionfor at least 2 hours, at least 4 hours, at least 6 hours, at least 8hours, at least 24 hours, at least 48 hours, or at least 72 hours.

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising the composition as prepared by a process asdescribed herein, and a pharmaceutically acceptable carrier.

In some embodiments, the present disclosure provides a method oftreating a cancer, the method comprising the step of administering to asubject in need thereof a therapeutically effective amount of thepharmaceutical composition as described herein.

In some embodiments, the cancer is a solid tumor. In some embodiments,the cancer is selected from the group consisting of breast cancer,non-small cell lung cancer, prostate cancer, gastric cancer, head andneck cancer, ovarian cancer, pancreatic cancer, and Kaposi's sarcoma.

EXAMPLES

Materials and Methods

HPLC Analysis:

The HPLC system used herein is a SHIMADZU LC-10AT vp series system,which consists of a SHIMADZU LC-10AT vp pump, a manual injector, aSHIMADZU CTO-10AS vp column oven, a SHIMADZU SPD-10A vp wavelengthdetector, and a SHIMADZU LC solution workstation. Waters XTERRA RP10column (4.6 mm×150 mm, 5 μm) is used as an analytical HPLC column. Thecolumn oven temperature is 30° C. Mobile phase is composed of methanoland water (70:30, v/v) and pumped at a flow rate of 1 ml/minute. Theeffluent is detected at a wavelength of 233 nm using a UV detector. Thesample injection amount is 20 μl.

Example 1: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Molar Ratio of Docetaxel to HSA Prepared was about 1:1.

Docetaxel (10 mg) was dissolved in methanol (10 ml) in a flask to give aclear solution. HSA (824 mg) (native fatty acid free human serum albuminpurchased from SeraCare Life Sciences, product code: HS-455-80, whichcontains fatty acids <0.2 mg/gm) as a powder was dissolved in 20 ml ofwater in a round bottom flask. The methanol solution of Docetaxel wasadded slowly dropwise into the flask of the HSA solution with rapidstirring. The addition took about 25 minutes to complete. Uponcompletion of the addition, a clear solution was obtained. The methanolwas removed under vacuum until the volume of the solution was about 18ml to give a clear solution. The resulting aqueous water solution waslyophilized overnight to give a white solid.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL water to give a clear solution. This clear water solution stays clearafter 24 hours without any solid precipitation.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL 2% ethanol water solution (2% ethanol in water) to give a clearsolution. This 2% ethanol water solution stays clear after 24 hourswithout any solid precipitation.

Example 2: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Molar Ratio of Docetaxel to HSA Prepared was about 1.3:1.

Docetaxel (3 mg) was dissolved in methanol (3 ml) in a glass vial togive a clear solution. HSA (190 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 6 mlof water in a round bottom flask. The methanol solution of Docetaxel wasadded slowly dropwise into the flask of the HSA solution with rapidstirring. The addition took about 8 minutes to complete. Upon completionof the addition, a clear solution was obtained. The methanol was removedunder vacuum until the volume of the solution was about 5 ml to give aclear solution. The resulting aqueous solution was lyophilized overnightto give a white solid.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL water to give a clear solution. This clear water solution stays clearwithout any solid precipitation after 24 hours at room temperature.

Example 3: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Molar Ratio of Docetaxel to HSA Prepared was about 1.5:1.

Docetaxel (3 mg) was dissolved in methanol (3 ml) in a glass vial togive a clear solution. HSA (165 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 6 mlof water in a round bottom flask. The methanol solution of Docetaxel wasadded slowly dropwise into the flask of the HSA solution with rapidstirring. The addition took about 8 minutes to complete. Upon completionof the addition, a clear solution was obtained. The methanol was removedunder vacuum until the volume of the solution was about 5 ml to give aclear solution. The resulting aqueous water solution was lyophilizedovernight to give a white solid.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL water to give a slightly cloudy solution.

Example 4: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Molar Ratio of Docetaxel to HSA Prepared was about 1.2:1.

Docetaxel (10 mg) was dissolved in methanol (5 ml) in a glass vial togive a clear solution. HSA (687 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 15ml of water in a round bottom flask. The methanol solution of Docetaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring. The addition took about 15 minutes to complete. Uponcompletion of the addition, a clear solution was obtained. The methanolwas removed under vacuum until the volume of the solution was about 13ml to give a clear solution. The clear water solution was filtered by a0.22 micron aqueous phase filter. The resulting clear aqueous solutionwas lyophilized overnight to give a white solid.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL water to give a clear solution. This clear water solution stays clearwith no precipitation of Docetaxel after 6 hours at room temperature.This clear water solution stays clear with no precipitation of Docetaxelafter 24 hours at room temperature. This clear water solution staysclear with no precipitation of Docetaxel after 3 days at roomtemperature.

A sample of 70 mg of the lyophilized solid was reconstituted by adding 1mL water to give a clear solution. This clear water solution stays clearwith no precipitation of Docetaxel after 6 hours at room temperature.This clear water solution stays clear with no precipitation of Docetaxelafter 24 hours at room temperature. This clear water solution staysclear with no precipitation of Docetaxel after 3 days at roomtemperature.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL water to give a clear solution. This clear water solution stays clearwith no precipitation of Docetaxel after 6 hours at 4° C. This clearwater solution stays clear with no precipitation of Docetaxel after 24hours at 4° C. This clear water solution stays clear with noprecipitation of Docetaxel after 3 days at 4° C.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL saline to give a clear solution. This clear saline solution staysclear with no precipitation of Docetaxel after 6 hours at roomtemperature. This clear saline solution stays clear with noprecipitation of Docetaxel after 24 hours at room temperature. Thisclear saline solution stays clear with no precipitation of Docetaxelafter 3 days at room temperature.

Example 5: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Molar Ratio of Docetaxel to HSA Prepared was about 1.2:1.

Docetaxel (3 mg) was dissolved in methanol (1.5 ml) in a glass vial togive a clear solution. HSA (206 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 4.5ml of water in a round bottom flask. The methanol solution of Docetaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring. The addition took about 4 minutes to complete. Upon completionof the addition, a clear solution was obtained. The clear solution wasfiltered by a 0.22 micron aqueous phase filter. The resulting clearaqueous solution with methanol was directly lyophilized overnight togive a white solid.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL water to give a clear solution. This clear water solution stays clearwith no precipitation of Docetaxel after 6 hours at room temperature.This clear water solution stays clear with no precipitation of Docetaxelafter 24 hours at room temperature. This clear water solution staysclear with no precipitation of Docetaxel after 3 days at roomtemperature.

Example 6: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Molar Ratio of Docetaxel to HSA Prepared was about 0.5:1.

Docetaxel (2 mg) was dissolved in methanol (1 ml) in a glass vial togive a clear solution. HSA (329 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 6 mlof water in a round bottom flask. The methanol solution of Docetaxel wasadded slowly dropwise into the flask of the HSA solution with rapidstirring. The addition took about 2-3 minutes to complete. Uponcompletion of the addition, a clear solution was obtained. The methanolwas removed under vacuum until the volume of the solution was about 5 mlto give a clear solution. The clear water solution was filtered by a0.22 micron aqueous phase filter. The resulting clear aqueous solutionwas lyophilized overnight to give a white solid.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL water to give a clear solution. This clear water solution stays clearwith no precipitation of Docetaxel after 6 hours at room temperature.This clear water solution stays clear with no precipitation of Docetaxelafter 24 hours at room temperature. This clear water solution staysclear with no precipitation of Docetaxel after 3 days at roomtemperature.

Example 7: Composition Comprising Docetaxel and Human Serum Albumin(Recombinant Human Serum Albumin

The Molar Ratio of Docetaxel to Recombinant Human Serum Albumin Preparedwas about 1:1.

Docetaxel (10 mg) was dissolved in methanol (7 ml) in a glass vial togive a clear solution. Recombinant human serum albumin (823 mg) (fattyacid free recombinant human serum albumin (no fatty acids detected)purchased from Wuhan Healthgen Biotechnology Corp., www.oryzogen.com) asa powder was dissolved in 16 ml of water in a round bottom flask. Themethanol solution of Docetaxel was added slowly dropwise into the flaskof the recombinant human serum albumin solution with rapid stirring.Upon completion of the addition, a clear solution was obtained. Themethanol was removed under vacuum until the volume of the solution wasabout 14 ml to give a clear solution. The clear water solution wasfiltered by a 0.22 micron aqueous phase filter. The resulting clearaqueous solution was lyophilized overnight to give a white solid.

A sample of 50 mg of the lyophilized solid was reconstituted by adding 1mL water to give a clear solution. This clear water solution stays clearwith no precipitation of Docetaxel after 6 hours at room temperature.This clear water solution stays clear with no precipitation of Docetaxelafter 24 hours at room temperature. This clear water solution staysclear with no precipitation of Docetaxel after 3 days at roomtemperature.

Example 8: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:85.

Docetaxel (10 mg) was dissolved in methanol (7 ml) in a glass vial togive a clear solution. HSA (850 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 17ml of water in a round bottom flask. The methanol solution of Docetaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring at 0° C. Upon completion of the addition, a clear solution wasobtained. Then, the methanol in the solution was removed under vacuum togive a clear solution. The clear water solution was filtered by a 0.22micron aqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution. This clear water solution staysclear with no precipitation of Docetaxel after 6 hours at roomtemperature. This clear water solution stays clear with no precipitationof Docetaxel after 24 hours at room temperature.

Example 9: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:90.

Docetaxel (50 mg) was dissolved in methanol (30 ml) in a glass vial togive a clear solution. HSA (4500 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 90ml of water in a round bottom flask. The methanol solution of Docetaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring at 0° C. Upon completion of the addition, a clear solution wasobtained. Additional 8.5 ml of methanol was added into the solution.Then, the methanol in the solution was removed under vacuum to give aclear solution. The clear water solution was filtered by a 0.22 micronaqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution. This clear water solution staysclear with no precipitation of Docetaxel after 6 hours at roomtemperature. This clear water solution stays clear with no precipitationof Docetaxel after 24 hours at room temperature.

Example 10: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:100.

Docetaxel (50 mg) was dissolved in methanol (30 ml) in a glass vial togive a clear solution. HSA (5000 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 100ml of water in a round bottom flask. The methanol solution of Docetaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring at 0° C. Upon completion of the addition, a clear solution wasobtained. Additional 13 ml of methanol was added into the solution.Then, the methanol in the solution was removed under vacuum to give aclear solution. The clear water solution was filtered by a 0.22 micronaqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution. This clear water solution staysclear with no precipitation of Docetaxel after 6 hours at roomtemperature. This clear water solution stays clear with no precipitationof Docetaxel after 24 hours at room temperature.

Example 11: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:100.

Docetaxel (5 mg) was dissolved in methanol (4.3 ml) in a glass vial togive a clear solution. HSA (500 mg) (native fatty acid free human serumalbumin purchased from Golden West Biologicals, Inc., CAT #: HA1020) asa powder was dissolved in 10 ml of water in a round bottom flask. Themethanol solution of Docetaxel was added slowly dropwise into the flaskof the HSA solution with rapid stirring at 0° C. Upon completion of theaddition, a clear solution was obtained. Then, the methanol in thesolution was removed under vacuum to give a clear solution. The clearwater solution was filtered by a 0.22 micron aqueous phase filter. Theresulting clear aqueous solution was lyophilized overnight to give awhite solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution. This clear water solution staysclear with no precipitation of Docetaxel after 3 hours at roomtemperature. This clear water solution stays clear with no precipitationof Docetaxel after 6 hours at room temperature. This clear watersolution stays clear with no precipitation of Docetaxel after 24 hoursat room temperature.

Example 12: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:200.

Docetaxel (1 mg) was dissolved in methanol (1.7 ml) in a glass vial togive a clear solution. HSA (200 mg) (native human serum albuminpurchased from Golden West Biologicals, Inc., CAT #: HA1000) as a powderwas dissolved in 4 ml of water in a round bottom flask. The methanolsolution of Docetaxel was added slowly dropwise into the flask of theHSA solution with rapid stirring at 0° C. Upon completion of theaddition, a clear solution was obtained. Then, the methanol in thesolution was removed under vacuum to give a clear solution. The clearwater solution was filtered by a 0.22 micron aqueous phase filter. Theresulting clear aqueous solution was lyophilized overnight to give awhite solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution with no precipitation of Docetaxel.

Example 13: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:150.

Docetaxel (1 mg) was dissolved in methanol (1 ml) in a glass vial togive a clear solution. HSA (150 mg) (native human serum albuminpurchased from Golden West Biologicals, Inc., CAT #: HA1000) as a powderwas dissolved in 3 ml of water in a round bottom flask. The methanolsolution of Docetaxel was added slowly dropwise into the flask of theHSA solution with rapid stirring at 0° C. Upon completion of theaddition, a clear solution was obtained. Then, the methanol in thesolution was removed under vacuum to give a clear solution. The clearwater solution was filtered by a 0.22 micron aqueous phase filter. Theresulting clear aqueous solution was lyophilized overnight to give awhite solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution with no precipitation of Docetaxel.

Example 14: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:150.

Docetaxel (2 mg) was dissolved in methanol (2.5 ml) in a glass vial togive a clear solution. A solution of HSA (300 mg, 1.5 ml) (20% humanserum albumin solution for infusion (product name: AlbuRx) from CSLBehring) was added into 4.5 ml of water to give a HSA solution (6 ml) ina round bottom flask. The methanol solution of Docetaxel was addedslowly dropwise into the flask of the HSA solution with rapid stirringat 0° C. Upon completion of the addition, a clear solution was obtained.Then, the methanol in the solution was removed under vacuum to give aclear solution. The clear water solution was filtered by a 0.22 micronaqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 15: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:160.

Docetaxel (2 mg) was dissolved in methanol (2.7 ml) in a glass vial togive a clear solution. A solution of HSA (320 mg, 1.6 ml) (20% humanserum albumin solution for infusion (product name: AlbuRx) from CSLBehring) was added into 4.8 ml of water to give a HSA solution (6.4 ml)in a round bottom flask. The methanol solution of Docetaxel was addedslowly dropwise into the flask of the HSA solution with rapid stirringat 0° C. Upon completion of the addition, a clear solution was obtained.Then, the methanol in the solution was removed under vacuum to give aclear solution. The clear water solution was filtered by a 0.22 micronaqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 16: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:170.

Docetaxel (2 mg) was dissolved in methanol (2.9 ml) in a glass vial togive a clear solution. A solution of HSA (340 mg, 1.7 ml) (20% humanserum albumin solution for infusion (product name: AlbuRx) from CSLBehring) was added into 5.1 ml of water to give a HSA solution (6.8 ml)in a round bottom flask. The methanol solution of Docetaxel was addedslowly dropwise into the flask of the HSA solution with rapid stirringat 0° C. Upon completion of the addition, a clear solution was obtained.Then, the methanol in the solution was removed under vacuum to give aclear solution. The clear water solution was filtered by a 0.22 micronaqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 17: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:180.

Docetaxel (2 mg) was dissolved in methanol (3.1 ml) in a glass vial togive a clear solution. A solution of HSA (360 mg, 1.8 ml) (20% humanserum albumin solution for infusion (product name: AlbuRx) from CSLBehring) was added into 5.4 ml of water to give a HSA solution (7.2 ml)in a round bottom flask. The methanol solution of Docetaxel was addedslowly dropwise into the flask of the HSA solution with rapid stirringat 0° C. Upon completion of the addition, a clear solution was obtained.Then, the methanol in the solution was removed under vacuum to give aclear solution. The clear water solution was filtered by a 0.22 micronaqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 18: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:200.

Docetaxel (2 mg) was dissolved in methanol (3.4 ml) in a glass vial togive a clear solution. A solution of HSA (400 mg, 2 ml) (20% human serumalbumin solution for infusion (product name: AlbuRx) from CSL Behring)was added into 6 ml of water to give a HSA solution (8 ml) in a roundbottom flask. The methanol solution of Docetaxel was added slowlydropwise into the flask of the HSA solution with rapid stirring at 0° C.Upon completion of the addition, a clear solution was obtained. Then,the methanol in the solution was removed under vacuum to give a clearsolution. The clear water solution was filtered by a 0.22 micron aqueousphase filter. The resulting clear aqueous solution was lyophilizedovernight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 19: Measure the Correlation Between HPLC Peak Area and theDocetaxel Concentration

Methanol solutions of Docetaxel in 7 different concentrations, 0.025mg/ml, 0.05 mg/ml, 0.075 mg/ml, 0.1 mg/ml, 0.15 mg/ml, 0.2 mg/ml and0.25 mg/ml, were prepared. The 7 Docetaxel methanol solutions wereanalyzed in HPLC. The peak area and concentration of Docetaxel werecorrelated using linear regression. The linear regression data is shownas below.Y (peak area)=61390+2.571E7*X (concentration), R=0.9999, P<0.0001.

Example 20: Measure the Docetaxel Concentrations in the Clear AqueousSolutions Before and after the Filtration at 0 Hour, and after theFiltration at 2 Hour, 4 Hour, 6 Hour, 8 Hour, 24 Hour, 48 Hour, and 72Hour

2.5 g of the lyophilized solid of the composition comprising Doectaxeland HSA (the ratio by weight about 1:100) from Example 10 was dissolvedin 50 ml of water to give a clear aqueous solution, which was kept atabout 20° C. Immediately after the lyophilized solid was dissolved inwater, 6 ml of the clear aqueous solution was taken out from the 50 mlsolution. Then 1 ml of the solution was taken out from the 6 ml clearaqueous solution to give the solution DC-0-0h, and the remaining 5 ml ofthe solution was filtered by the same 0.22 micron aqueous phase filterat 1 ml at a time to give the solutions DC-1-0h, DC-2-0h, DC-3-0h,DC-4-0h, and DC-5-0h. To 200 μl of the solutions DC-0-0h and DC-5-0hwere added 800 μl of acetonitrile separately. The mixtures were vortexedfor seconds and then centrifuged at 4,000 g for 5 minutes. Thesupernatants were removed and collected followed by injection on HPLC.The same procedure was repeated 2 more times for each of solutionsDC-0-0h and DC-5-0h. Based on the HPLC data and the measurement data ofExample 19, the Docetaxel concentrations of the solutions of DC-0-0h,and DC-5-0h have been calculated and shown in the Table 1. At 0 hour,the Docetaxel concentration of the clear aqueous solution after thefiltration was about 100.4% of the Docetaxel concentration of the clearaqueous solution before the filtration.

TABLE 1 Docetaxel Average Docetaxel Solution Number Concentration(mg/ml) Concentration (mg/ml) DC-0-0h-1 0.4939 0.4908 DC-0-0h-2 0.4902DC-0-0h-3 0.4884 DC-5-0h-1 0.4964 0.4926 DC-5-0h-2 0.4902 DC-5-0h-30.4913At 2 hour, 5 ml of the clear aqueous solution was taken out from theremaining 44 ml of the aqueous solution. Then 1 ml of the solution wastaken out from the 5 ml clear aqueous solution and filtered by a 0.22micron aqueous phase filter to give the solution DC-1-2h, and theremaining 4 ml of the solution was filtered by the same 0.22 micronaqueous phase filter at 1 ml at a time to give the solutions DC-2-2h,DC-3-2h, DC-4-2h, and DC-5-2h. To 200 μl of the solution DC-5-2h wasadded 800 μl of acetonitrile. The mixture was vortexed for seconds andthen centrifuged at 4,000 g for 5 minutes. The supernatant was removedand collected followed by injection on HPLC. The same procedure wasrepeated 2 more times for the solution DC-5-2h. Based on the HPLC dataand the measurement data of Example 19, the Docetaxel concentrations ofthe solution DC-5-2h have been calculated and shown in the Table 2. At 2hour, the Docetaxel concentration of the clear aqueous solution afterthe filtration was about 100% of the Docetaxel concentration of theclear aqueous solution at 0 hour before the filtration.

TABLE 2 Docetaxel Concentration Average Docetaxel Solution Number(mg/ml) Concentration (mg/ml) DC-5-2h-1 0.4898 0.4908 DC-5-2h-2 0.4910DC-5-2h-3 0.4916At 4 hour, 5 ml of the clear aqueous solution was taken out from theremaining 39 ml of the aqueous solution. The experiments were done forthe 5 ml of the clear aqueous solution taken out at 4 hour using thesame protocol as for the 5 ml of the clear aqueous solution taken out at2 hour. Based on the HPLC data and the measurement data of Example 19,the Docetaxel concentrations of the solution DC-5-4h have beencalculated and shown in the Table 3. At 4 hour, the Docetaxelconcentration of the clear aqueous solution after the filtration wasabout 99.96% of the Docetaxel concentration of the clear aqueoussolution at 0 hour before the filtration.

TABLE 3 Docetaxel Concentration Average Docetaxel Solution Number(mg/ml) Concentration (mg/ml) DC-5-4h-1 0.4903 0.4906 DC-5-4h-2 0.4913DC-5-4h-3 0.4903At 6 hour, 5 ml of the clear aqueous solution was taken out from theremaining 34 ml of the aqueous solution. The experiments were done forthe 5 ml of the clear aqueous solution taken out at 6 hour using thesame protocol as for the 5 ml of the clear aqueous solution taken out at2 hour. Based on the HPLC data and the measurement data of Example 19,the Docetaxel concentrations of the solution DC-5-6h have beencalculated and shown in the Table 4. At 6 hour, the Docetaxelconcentration of the clear aqueous solution after the filtration wasabout 99.84% of the Docetaxel concentration of the clear aqueoussolution at 0 hour before the filtration.

TABLE 4 Docetaxel Concentration Average Docetaxel Solution Number(mg/ml) Concentration (mg/ml) DC-5-6h-1 0.4899 0.4900 DC-5-6h-2 0.4900DC-5-6h-3 0.4900At 8 hour, 5 ml of the clear aqueous solution was taken out from theremaining 29 ml of the aqueous solution. The experiments were done forthe 5 ml of the clear aqueous solution taken out at 8 hour using thesame protocol as for the 5 ml of the clear aqueous solution taken out at2 hour. Based on the HPLC data and the measurement data of Example 19,the Docetaxel concentrations of the solution DC-5-8h have beencalculated and shown in the Table 5. At 8 hour, the Docetaxelconcentration of the clear aqueous solution after the filtration wasabout 99.27% of the Docetaxel concentration of the clear aqueoussolution at 0 hour before the filtration.

TABLE 5 Docetaxel Concentration Average Docetaxel Solution Number(mg/ml) Concentration (mg/ml) DC-5-8h-1 0.4856 0.4872 DC-5-8h-2 0.4879DC-5-8h-3 0.4882

At 24 hour, 5 ml of the clear aqueous solution was taken out from theremaining 24 ml of the aqueous solution. The experiments were done forthe 5 ml of the clear aqueous solution taken out at 24 hour using thesame protocol as for the 5 ml of the clear aqueous solution taken out at2 hour. Based on the HPLC data and the measurement data of Example 19,the Docetaxel concentrations of the solution DC-5-24h have beencalculated and shown in the Table 6. At 24 hour, the Docetaxelconcentration of the clear aqueous solution after the filtration wasabout 96.05% of the Docetaxel concentration of the clear aqueoussolution at 0 hour before the filtration.

TABLE 6 Docetaxel Concentration Average Docetaxel Solution Number(mg/ml) Concentration (mg/ml) DC-5-24h-1 0.4710 0.4714 DC-5-24h-2 0.4720DC-5-24h-3 0.4712At 48 hour, 5 ml of the clear aqueous solution was taken out from theremaining 19 ml of the aqueous solution. The experiments were done forthe 5 ml of the clear aqueous solution taken out at 24 hour using thesame protocol as for the 5 ml of the clear aqueous solution taken out at2 hour. Based on the HPLC data and the measurement data of Example 19,the Docetaxel concentrations of the solution DC-5-48h have beencalculated and shown in the Table 7. At 48 hour, the Docetaxelconcentration of the clear aqueous solution after the filtration wasabout 89.10% of the Docetaxel concentration of the clear aqueoussolution at 0 hour before the filtration.

TABLE 7 Docetaxel Concentration Average Docetaxel Solution Number(mg/ml) Concentration (mg/ml) DC-5-48h-1 0.4370 0.4373 DC-5-48h-2 0.4380DC-5-48h-3 0.4370At 72 hour, 5 ml of the clear aqueous solution was taken out from theremaining 14 ml of the aqueous solution. The experiments were done forthe 5 ml of the clear aqueous solution taken out at 24 hour using thesame protocol as for the 5 ml of the clear aqueous solution taken out at2 hour. Based on the HPLC data and the measurement data of Example 19,the Docetaxel concentrations of the solution DC-5-72h have beencalculated and shown in the Table 8. At 72 hour, the Docetaxelconcentration of the clear aqueous solution after the filtration wasabout 75.57% of the Docetaxel concentration of the clear aqueoussolution at 0 hour before the filtration.

TABLE 8 Docetaxel Concentration Average Docetaxel Solution Number(mg/ml) Concentration (mg/ml) DC-5-72h-1 0.3707 0.3708 DC-5-72h-2 0.3703DC-5-72h-3 0.3713

Example 21: Pharmacokinetics Study of Composition Comprising Docetaxeland Human Serum Albumin (HSA)

A group of 3 Sprague Dawley® (“SD”) male rats were used inpharmacokinetics study. The dosing route of the study was IV. The dosefor the PK study of the composition comprising Docetaxel and HSA (theratio by weight of Docetaxel to HSA in the composition is about 1:85)was 680 mg/kg. The 11 time points for the study were 0.083, 0.25, 0.5,1, 2, 4, 8, 12, 24, 36 and 48 hr post dose. All blood samples werecollected from carotid artery cannula. Blood samples were transferredinto EDTA-K2 anti-coagulant tube and immediately placed on ice. Bloodsamples will be processed for plasma by centrifugation at approximately4° C., 3000 g within half an hour of collection. Plasma samples will bestored in polypropylene tubes, quick frozen over dry ice and kept at−70±10° C. until LC/MS/MS analysis.

An LC-MS/MS method was developed for Docetaxel in male SD rat plasma.Table 9 shows the PK parameters of the PK study. FIG. 1 shows meanplasma concentration-time data for Docetaxel after an IV dose of 680mg/kg of the composition comprising Docetaxel and HSA in SD rats.

TABLE 9 CL (mL/min/kg) Vdss (L/kg) T_(1/2) (hr) AUC_(0-last) (ng · h/mL)140 112 15.8 600

Example 22: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:100.

Docetaxel (100 mg) was dissolved in methanol (42.9 ml) in a glass vialto give a clear solution. HSA (10 g) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 100ml of water in a round bottom flask. The methanol solution of Docetaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring at 0° C. Upon completion of the addition, a clear solution wasobtained. Then, the methanol in the solution was removed under vacuum togive a clear solution. The clear aqueous solution was filtered by a 0.22micron aqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 23: Composition Comprising Docetaxel and Human Serum Albumin(HSA) the Ratio by Weight of Docetaxel to HSA Prepared was about 1:180

Docetaxel (10 mg) was dissolved in methanol (15.4 ml) in a glass vial togive a clear solution. A solution of HSA (1800 mg, 9 ml) (20% humanserum albumin solution for infusion (product name: AlbuRx) from CSLBehring) was added into 27 ml of water to give a HSA solution (36 ml) ina round bottom flask. The methanol solution of Docetaxel was addedslowly dropwise into the flask of the HSA solution with rapid stirringat 0° C. Upon completion of the addition, a clear solution was obtained.Then, the methanol in the solution was removed under vacuum to give aclear solution. The clear aqueous solution was filtered by a 0.22 micronaqueous phase filter. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 24: Composition Comprising Docetaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Docetaxel to HSA Prepared was about 1:100.

Docetaxel (10 mg) was dissolved in methanol (8.6 ml) in a glass vial togive a clear solution. HSA (1000 mg) (native fatty acid free human serumalbumin purchased from Golden West Biologicals, Inc., CAT #: HA1020) asa powder was dissolved in 20 ml of water in a round bottom flask. Themethanol solution of Docetaxel was added slowly dropwise into the flaskof the HSA solution with rapid stirring at 0° C. Upon completion of theaddition, a clear solution was obtained. Then, the methanol in thesolution was removed under vacuum to give a clear solution. The clearaqueous solution was filtered by a 0.22 micron aqueous phase filter. Theresulting clear aqueous solution was lyophilized overnight to give awhite solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 25: Measure pH Value of the Clear Aqueous Solution ofComposition Comprising Docetaxel and Human Serum Albumin (HSA)

250 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of water to give a clear aqueous solution. The clear aqueoussolution was kept at about 25° C. and measured for pH value. The pHvalue of the clear aqueous solution is 6.72 (3 measurements: 6.71, 6.72,and 6.72).

500 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of water to give a clear aqueous solution. The clear aqueoussolution was kept at about 25° C. and measured for pH value. The pHvalue of the clear aqueous solution is 6.73 (3 measurements: 6.73, 6.74,and 6.73).

750 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of water to give a clear aqueous solution. The clear aqueoussolution was kept at about 25° C. and measured for pH value. The pHvalue of the clear aqueous solution is 6.75 (3 measurements: 6.75, 6.75,and 6.76).

250 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of 0.9% saline solution, which had pH value about 5.41, to givea clear aqueous solution. The clear aqueous solution was kept at about25° C. and measured for pH value. The pH value of the clear aqueoussolution is 6.74 (3 measurements: 6.73, 6.74, and 6.74).

500 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of 0.9% saline solution, which had pH value about 5.41, to givea clear aqueous solution. The clear aqueous solution was kept at about25° C. and measured for pH value. The pH value of the clear aqueoussolution is 6.75 (3 measurements: 6.74, 6.75, and 6.76).

750 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of 0.9% saline solution, which had pH value about 5.41, to givea clear aqueous solution. The clear aqueous solution was kept at about25° C. and measured for pH value. The pH value of the clear aqueoussolution is 6.78 (3 measurements: 6.77, 6.79, and 6.78).

250 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of 5% Dextrose solution, which had pH value about 4.40, to givea clear aqueous solution. The clear aqueous solution was kept at about25° C. and measured for pH value. The pH value of the clear aqueoussolution is 6.67 (3 measurements: 6.67, 6.66, and 6.67).

500 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of 5% Dextrose solution, which had pH value about 4.40, to givea clear aqueous solution. The clear aqueous solution was kept at about25° C. and measured for pH value. The pH value of the clear aqueoussolution is 6.75 (3 measurements: 6.73, 6.75, and 6.76).

750 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 22 was dissolvedin 10 ml of 5% Dextrose solution, which had pH value about 4.40, to givea clear aqueous solution. The clear aqueous solution was kept at about25° C. and measured for pH value. The pH value of the clear aqueoussolution is 6.76 (3 measurements: 6.75, 6.76, and 6.76).

Example 26: Measure pH Value of the Clear Aqueous Solution ofComposition Comprising Docetaxel and Human Serum Albumin (HSA)

500 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:180) from Example 23 was dissolvedin 10 ml of water to give a clear aqueous solution. The clear aqueoussolution was kept at about 25° C. and measured for pH value. The pHvalue of the clear aqueous solution is 7.10 (3 measurements: 7.09, 7.10,and 7.11).

Example 27: Measure pH Value of the Clear Aqueous Solution ofComposition Comprising Docetaxel and Human Serum Albumin (HSA)

250 mg of the lyophilized solid of the composition comprising Docetaxeland HSA (the ratio by weight about 1:100) from Example 24 was dissolvedin 10 ml of water to give a clear aqueous solution. The clear aqueoussolution was kept at about 25° C. and measured for pH value. The pHvalue of the clear aqueous solution is 6.85 (3 measurements: 6.86, 6.84,and 6.85).

Example 28: Composition Comprising Paclitaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Paclitaxel to HSA Prepared was about 1:240.

Paclitaxel (2 mg) was dissolved in methanol (4.3 ml) in a glass vial togive a clear solution. HSA (480 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 10ml of water in a round bottom flask. The methanol solution of Paclitaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring at 0° C. Upon completion of the addition, a clear solution wasobtained. Then, the methanol in the solution was removed under vacuum togive a clear solution. The resulting clear aqueous solution waslyophilized overnight to give a white solid.

A sample of 100 mg of the lyophilized solid was reconstituted by adding2 mL water to give a clear solution.

Example 29: Composition Comprising Paclitaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Paclitaxel to HSA Prepared was about 1:200.

Paclitaxel (3 mg) was dissolved in methanol (5.1 ml) in a glass vial togive a clear solution. HSA (600 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 12ml of water in a round bottom flask. The methanol solution of Paclitaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring at 0° C. Upon completion of the addition, a clear solution wasobtained. Then, the methanol in the solution was removed under vacuum togive a clear solution. The resulting clear aqueous solution waslyophilized overnight to give a white solid. A sample of 100 mg of thelyophilized solid was reconstituted by adding 2 mL water to give acloudy solution.

Example 30: Composition Comprising Paclitaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Paclitaxel to HSA Prepared was about 1:160.

Paclitaxel (3 mg) was dissolved in methanol (4.3 ml) in a glass vial togive a clear solution. HSA (480 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 10ml of water in a round bottom flask. The methanol solution of Paclitaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring at 0° C. Upon completion of the addition, a clear solution wasobtained. Then, the methanol in the solution was removed under vacuum togive a clear solution. The resulting clear aqueous solution waslyophilized overnight to give a white solid. A sample of 100 mg of thelyophilized solid was reconstituted by adding 2 mL water to give acloudy solution. The solution stayed cloudy and formed the whiteprecipitations in about 2 hours.

Example 31: Composition Comprising Paclitaxel and Human Serum Albumin(HSA)

The Ratio by Weight of Paclitaxel to HSA Prepared was about 1:120.

Paclitaxel (3 mg) was dissolved in methanol (3 ml) in a glass vial togive a clear solution. HSA (360 mg) (native fatty acid free human serumalbumin purchased from SeraCare Life Sciences, product code: HS-455-80,which contains fatty acids <0.2 mg/gm) as a powder was dissolved in 7 mlof water in a round bottom flask. The methanol solution of Paclitaxelwas added slowly dropwise into the flask of the HSA solution with rapidstirring at 0° C. Upon completion of the addition, a clear solution wasobtained. After the methanol in the solution was removed under vacuum, acloudy solution was obtained.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A pharmaceutical composition comprising anon-covalently bound complex comprising Docetaxel and human serumalbumin, wherein the molar ratio of Docetaxel and the human serumalbumin in the composition is from about 0.1:1 to about 5:1, wherein thecomposition is a clear aqueous solution, wherein the human serum albuminin the composition is from commercial pharmaceutical human serum albuminsolution for infusion, wherein the docetaxel concentration in thesolution is higher than aqueous solubility of docetaxel, and wherein pHof the composition is from about 5 to about
 8. 2. The composition ofclaim 1, wherein the molar ratio of Docetaxel and the human serumalbumin is from about 0.5:1 to about 2:1.
 3. The composition of claim 1,wherein the molar ratio of Docetaxel and the human serum albumin isabout 1:1.
 4. The composition of claim 1, wherein pH of the compositionis from about 5.5 to about 7.5.
 5. A method for the preparation of thecomposition of claim 1, said method comprising: mixing an organicsolution of Docetaxel in a polar water-miscible organic solvent and afirst aqueous solution containing human serum albumin to form a secondaqueous solution, wherein the second aqueous solution is a clear aqueoussolution.
 6. The method of claim 5, further comprising removing saidpolar water miscible organic solvent and water from the second aqueoussolution.
 7. A pharmaceutical composition comprising Docetaxel and humanserum albumin, wherein the Docetaxel and the human serum albumin in thecomposition have a ratio by weight from about 1:50 to about 1:1000,wherein the composition is a clear aqueous solution, wherein the humanserum albumin in the composition is from commercial pharmaceutical humanserum albumin solution for infusion, wherein the docetaxel concentrationin the solution is higher than aqueous solubility of docetaxel, andwherein pH of the composition is from about 5 to about
 8. 8. Thecomposition of claim 7, wherein the Docetaxel and the human serumalbumin in the composition have a ratio by weight from about 1:60 toabout 1:300.
 9. The composition of claim 7, wherein the Docetaxel andthe human serum albumin in the composition have a ratio by weight fromabout 1:80 to about 1:200.
 10. The composition of claim 7, wherein thecomposition is substantially free of solvent other than water.
 11. Thecomposition of claim 7, wherein the composition is a clear aqueoussolution for at least 3 hours.
 12. A method of treating a cancer, themethod comprising the step of administering to a subject in need thereofa therapeutically effective amount of a pharmaceutical composition ofclaim
 1. 13. The method of claim 12, wherein the cancer is selected fromthe group consisting of breast cancer, non-small cell lung cancer,prostate cancer, gastric cancer, head and neck cancer, ovarian cancer,pancreatic cancer, and Kaposi's sarcoma.